Trk-inhibiting compound

ABSTRACT

The present invention provides a drug containing a compound having Trk-inhibiting activity as an active ingredient in prophylaxis and/or therapy for Trk-related diseases such as pain, pruritus, lower urinary tract dysfunction, asthma, allergic rhinitis, inflammatory bowel disease or Chagas disease. A compound represented by the general formula (I), wherein all symbols represent the same meanings as described in the specification, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof is useful as a drug component having Trk-inhibiting activity in prophylaxis and/or therapy of diseases such as pain, pruritus, lower urinary tract dysfunction, asthma, allergic rhinitis, inflammatory bowel disease or Chagas disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/173,161, filed Jun. 3, 2016, which is a continuation of U.S. patentapplication Ser. No. 14/768,727, filed Aug. 18, 2015 (now U.S. Pat. No.9,463,192), which is a National Phase of PCT/JP2014/053683, filed Feb.18, 2014, which claims priority to Japanese Application No. 2013-029563,filed Feb. 19, 2013 and Japanese Application No. 2013-141246, filed Jul.5, 2013, the entireties of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a Trk-inhibiting compound or a saltthereof and a medicament containing the same as an active ingredient.More specifically, the present invention relates to a Trk-inhibitingcompound represented by the general formula (I):

wherein all symbols represent the same meanings as describedhereinbelow, and a salt thereof, an N-oxide thereof, a solvate thereofor a prodrug thereof (hereinafter referred to as “the present compound”)and a medicament containing the same as an active ingredient.

BACKGROUND ART

The tropomyosin receptor kinase (hereinafter abbreviated as “Trk”)family is classified as receptor tyrosine kinases and comprises TrkAwhich is a high-affinity receptor of nerve growth factor (hereinafterabbreviated as NGF), TrkB which is a high-affinity receptor ofbrain-derived neutrophic factor (BDNF) and neurotrophin (hereinafterabbreviated as NT)-4/5 and TrkC which is a high-affinity receptor ofNT-3. All Trk receptors are highly expressed in nerve tissues and areinvolved in differentiation and maintenance of functions of nerve cells(see Non-Patent Document 1). Meanwhile it has been known that activationof TrkA in peripheral nerves by NGF initiates hyperalgesia (seeNon-Patent Document 2) and based on clinical and non-clinical testresults using anti-NGF antibodies and non-clinical test results usinglow-molecular weight Trk inhibitors, involvement of TrkA has beenreported in nociceptive pain of osteoarthritis, chronic low back pain,rheumatoid arthritis, bone fracture, interstitial cystitis and chronicpancreatitis, neuropathic pain as well as cancer pain combining bothtypes of pain described above (see Non-Patent Document 3 to 10).Moreover, Trk receptors are expressed on cancer cells such asneuroblastoma, prostate cancer and pancreatic cancer, inflammatory cellssuch as mast cells and eosinophils, immunocompetent cells such as Tcells and B cells and keratinocytes and are reported to be potentiallyinvolved in proliferation, migration and metastasis of cancer cells,inflammatory diseases such as ulcerative colitis and Crohn's disease,allergic diseases such as asthma, rhinitis and atopic dermatitis andother diseases such as psoriasis (see Non-Patent Document 11 to 15).Therefore compounds having Trk-inhibiting activity may be applied totherapy of nociceptive pain, neuropathic pain and pain combining bothtypes of pain, cancer, inflammatory diseases, allergic diseases andpsoriasis.

Accordingly it is expected that development of Trk-inhibiting agents mayprovide novel types of prophylactic and/or therapeutic agents for painand the like.

Meanwhile Patent Document 1 discloses a method for treating orpreventing a disease in a human or other mammal regulated by tyrosinekinase, comprising administering, to a human or other mammal in needthereof, a compound of the following formula (Ia), a salt thereof, anisomer thereof or a prodrug.

The general formula (Ia) is as follows:

wherein Aa is selected from the group consisting of the following (i) to(iii) and the like;

(i)phenyl, optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of Ra¹, ORa¹, a halogen and the like;

(ii) naphthyl, optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of Ra¹, ORa¹, a halogenand the like;

(iii) a 5- to 6-membered monocyclic heteroaryl group, optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of Ra¹, ORa¹, a halogen and the like and having 1 to 3heteroatoms independently selected from the group consisting of O, N andS;

Ba is selected from the group consisting of the following (i) to (iii)and the like;

(i)phenyl, optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of —La-Ma, C₁-C₅ linear or branchedalkyl, halogen and the like;

(ii) naphthyl, optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of —La-Ma, a C₁-C₅linear or branched alkyl, a halogen and the like;

(iii) a 5- to 6-membered monocyclic heteroaryl group, optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of —La-Ma, a C₁-C₅ linear or branched alkyl, a halogenand the like and having 1 to 3 heteroatoms independently selected fromthe group consisting of O, N and S;

La is selected from the group consisting of —(CH₂)_(ma)—O—(CH₂)_(1a)—,—(CH₂)_(ma)—C(O)— (CH₂)_(1a)— and the like, wherein the variables ma andla are integers independently selected from 0 to 4;

Ma is selected from the group consisting of the following (i) to (iii)and the like;

(i)phenyl, optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of Ra¹, ORa¹, a halogen and the like;

(ii) naphthyl, optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of Ra¹, ORa¹, a halogenand the like;

(iii) a 5- to 6-membered monocyclic heteroaryl group, optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of Ra¹, ORa¹, a halogen and the like and having 1 to 3heteroatoms independently selected from the group consisting of O, N andS;

wherein Ra¹ is independently selected from the group consisting of (a) ahydrogen, (b) a C₁-C₆ alkyl, (c)phenyl, (d) a 5- to 6-memberedmonocyclic heteroaryl or a 8- to 10-membered bicyclic heteroaryl bothhaving 1 to 4 heteroatoms selected from the group consisting of O, N andS, (e) a C₁-C₃ alkyl-phenyl and (f) an alkyl-heteroaryl having 1 to 4heteroatoms selected from the group consisting of O, N and S; Ra¹ is,when it is not a hydrogen, optionally substituted with 1 to 3substituents independently selected from the group consisting of a C₁-C₅linear, branched or cyclic alkyl, a C₁-C₃ alkoxy, hydroxy, amino, aC₁-C₃ alkylamino, a C₂-C₆ dialkylamino, a halogen, cyano and nitro; andthe definitions of the groups are partially abstracted.

Patent Document 1 discloses that the compound therein inhibits KDR andthereby is used for a method of treatment of diseases mediated by VEGFinduced signal transduction pathways in a human or other mammal,particularly retinopathy or retinopathy of prematurity. However, it isnot disclosed or suggested that the compound disclosed therein hasTrk-inhibiting activity and Patent Document 1 does not specificallydisclose the present compound.

Patent Document 2 discloses that a compound represented by the generalformula (Ib):

wherein:

Yb is N or CH;

Lb¹ is a bond, —O—, —S—, —SO—, —SO₂— or the like;

Lb² is a bond, —NHC(O)NH—, —NHC(O)— or the like;

Rb¹ is (i) Rb⁵ or (ii) a C₁-C₆ alkyl optionally substituted with one ormore halogen, Rb⁵ or the like;

Rb² is (i) a C₁-C₆ alkyl or (ii) an aryl or heteroaryl, each of which isoptionally substituted with one or more halogen, Rb⁹, ORb⁹, SRb⁹,N(Rb⁹)₂, C(O)Rb⁹ or the like;

Rb³ is a hydrogen, a halogen, a C₁-C₆ alkyl or the like;

Rb⁵ is a cycloalkyl, a heterocycle, an aryl or a heteroaryl, each ofwhich is optionally substituted with one or more halogen, ORb⁶, N(Rb⁶)₂,Rb⁷, ORb⁷ or the like;

Rb⁷ is a cycloalkyl, a heterocycle, an aryl or a heteroaryl, each ofwhich is optionally substituted with one or more halogen, hydroxy,N(Rb⁶)₂ or the like; and

each Rb⁶ is independently a hydrogen or a C₁-C₄ alkyl (the definitionsof the groups are partially abstracted), a tautomer, enantiomer,pharmaceutically acceptable salt, hydrate, solvate, complex or a prodrugthereof acts as an endogenous utrophin upregulator. However, it is notdisclosed or suggested that the compounds have Trk-inhibiting activity.In addition, Patent Document 2 does not specifically disclose thepresent compound.

Further, Patent Document 3 discloses that a compound represented by thegeneral formula (Ic):

wherein:

Ac and Cc are each independently selected from the group consisting ofan aryl and heteroaryl, both of which may be optionally substituted;

Bc is selected from the group consisting of —N(H)C(O)N(H)— and—N(H)C(O)N(H)CH₂—;

Xc¹ to Xc⁴ are each selected from the group consisting of C(Rc²) and Nand at least one of Xc¹ to Xc⁴ is N;

Xc⁵ is C(Rc³) (Rc⁴), N(Rc³), O or S(O)_(mc); and

Rc¹ is selected from the group consisting of a heteroaryl andheterocycloalkyl, both of which may be optionally substituted (thedefinitions of the groups are partially abstracted), a salt or esterthereof or a prodrug thereof has B-Raf-inhibiting activity. However, itis not disclosed or suggested that the compounds have Trk-inhibitingactivity. In addition, Patent Document 3 does not disclose the presentcompound.

None of the Trk-inhibiting compounds which have been known by now has achemical structure characterized by “urea group-ring-O-ring-ring” as thecompounds of the present invention.

-   Patent Document 1: WO 2003/068228-   Patent Document 2: WO 2010/057833-   Patent Document 3: WO 2007/076473-   Non-Patent Document 1: Annual Review of Biochemistry, 72, 609-642,    2003-   Non-Patent Document 2: Trends in Pharmacological Sciences, 27,    85-91, 2006-   Non-Patent Document 3: New England Journal of Medicine, 363,    1521-1531, 2010-   Non-Patent Document 4: Pain, 152, 2248-2258, 2011-   Non-Patent Document 5: Journal of Urology, 185, 1716-1721, 2011-   Non-Patent Document 6: Pain, 116, 8-16, 2005-   Non-Patent Document 7: Bone, 48, 389-398, 2011-   Non-Patent Document 8: Molecular Pain, 6, 87, 2010-   Non-Patent Document 9: Journal of Pharmacological and Experimental    Therapeutics, 322, 282-287, 2007-   Non-Patent Document 10: Gastroenterology, 141, 370-377, 2011-   Non-Patent Document 11: Expert Opinion Therapeutic Patents, 19,    305-319, 2009-   Non-Patent Document 12: Gut, 46, 670-679, 2000-   Non-Patent Document 13: Current Opinion in Allergy and Clinical    Immunology, 10, 8-13, 2010-   Non-Patent Document 14: Inflammation and Allergy Drug Targets, 9,    173-180, 2010-   Non-Patent Document 15: Journal of Investigative Dermatology, 126,    1719-1727, 2006

DISCLOSURE OF THE INVENTION

An object of the present invention is to create a compound havingselective Trk-inhibiting activity and find a compound useful as aprophylactic and/or therapeutic agent for various diseases typicallyincluding pain.

The present inventors have carried out exhaustive studies in order tofind compounds which have selective Trk-inhibiting activity and can beprophylactic and/or therapeutic agents for various diseases typicallyincluding pain, and as a result have found that the compoundsrepresented by the following general formula (I) have Trk-inhibitingaction, have excellent kinase selectivity and can persistently inhibitNGF vascular hyper permeability, thereby completing the presentinvention.

Thus the present invention relates to the followings:

[1] A compound represented by the general formula (I):

a compound represented by the general formula (I):wherein:a ring Cy₁ represents a C3-10 monocyclic carbocycle or bicycliccarbocycle or a 4- to 10-membered monocyclic heterocycle or bicyclicheterocycle;a ring Cy₂ represents a 4- to 10-membered monocyclic heterocycle orbicyclic heterocycle excluding a heterocycle 1,3-thiazol-5-yl group;R₁ represents:(1) a halogen;(2) a C1-6 alkyl group, C2-6 alkenyl group or C2-6 alkynyl groupoptionally substituted with a substituent selected from the groupconsisting of (i) a halogen and (ii) a hydroxy group;(3) a C5-6 monocyclic carbocycle optionally substituted with one or twoR₅ groups;(4) a 5- to 6-membered monocyclic heterocycle optionally substitutedwith one or two R₅ groups;(5) —S(O)_(m1)—R₆;(6) —SO₂NR₇R₈;(7) —C(O)OR₉;(8) —NR₁₀C(O)R₁₁;(9) —C(O)NR₁₂R₁₃;(10) —OR₁₄;(11) —NR₁₅R₁₆;(12) a cyano group; or(13) a nitro group;R₅ represents:(1) a halogen;(2) —S(O)_(m2)—R₁₇;(3) —SO₂NR₁₈R₁₉;(4) —C(O)OR₂₀;(5) —NR₂₁C(O)R₂₂;(6) —C(O)NR₂₃R₂₄;(7) —OR₂₅;(8) —NR₂₆R₂₇;(9) a cyano group;(10) a nitro group; or(11) a C1-3 alkyl group optionally substituted with a substituentselected from the group consisting of (i) a halogen, (ii) a hydroxygroup and (iii) an oxo group; when two R₅ groups are present, the R₅groups may be independently the same or different;when, further, two R₅ groups are respectively and independently a C1-3alkyl group or a hydroxy group and the R₅ groups are attached to carbonatoms adjacent to each other on the C5-6 monocyclic carbocycle or the 5-to 6-membered monocyclic heterocycle, the R₅ groups may together form aring;R₆ to R₂₇ respectively and independently represent (1) a hydrogen atomor (2) a C1-6 alkyl group optionally substituted with (i) a halogen or(ii) a hydroxy group;when R₁₈ and R₁₉ are respectively and independently a C1-6 alkyl group,R₁₈ and R₁₉ groups may together form a ring;R₂ represents:

-   -   (1) a halogen;        (2) a C1-6 alkyl group optionally substituted with (i) a halogen        or (ii) a hydroxy group;        (3) a C3-6 cycloalkyl group optionally substituted with (i) a        halogen or (ii) a hydroxy group;        (4) a C1-6 alkoxy group optionally substituted with a halogen;        (5) —NR₂₈R₂₉;        (6) a 3- to 7-membered monocyclic heterocycle; or        (7) —O-(3- to 7-membered monocyclic heterocycle);        R₂₈ and R₂₉ respectively and independently represent (1) a        hydrogen atom or (2) a C1-6 alkyl group optionally substituted        with (i) a halogen or (ii) a hydroxy group;        A₁ and A₂ respectively and independently represent ═CR₃— or ═N—;        A₃, A₄, A₅ and A₆ respectively and independently represent ═CR₄—        or ═N—;        R₃ and R₄ respectively and independently represent a hydrogen        atom or a halogen;        m1 represents an integer of 0 to 2;        m2 represents an integer of 0 to 2;        p represents an integer of 0 to 7;        q represents an integer of 0 to 7;        r represents an integer of 0 to 2;        provided that when p, q and r respectively represent an integer        of 2 or more, R₁, R₂ and R₃ groups may be respectively and        independently the same or different, a salt thereof, an N-oxide        thereof, a solvate thereof or a prodrug thereof;        [2] the compound according to the above [1], wherein the ring        Cy₂ is a 5- to 10-membered monocyclic aromatic heterocycle or        bicyclic aromatic heterocycle excluding a heterocycle        1,3-thiazol-5-yl group;        [3] the compound according to the above [1] or [2], wherein the        ring Cy₂ is a pyridine ring, a pyrimidine ring, a        pyrazolopyrimidine ring, an imidazopyridazine ring, an        imidazopyridine ring, a pyrrolopyridine ring, an imidazopyrazine        ring or a pyrazolopyridine ring;        [4] the compound according to any one of the above [1] to [3],        wherein one of A₁ and A₂ is ═N— and the other is ═CH— or both        are ═N— and A₃, A₄, A₅ and A₆ are ═CH—;        [5] the compound according to the above [1], wherein the general        formula (I) is represented by the general formula (I-i) or the        general formula (I-ii):

wherein R_(2-a) represents the same meaning as R₂; q-a represents aninteger of 0 to 3; t represents an integer of 0 to 4; and other symbolsrepresent the same meanings as those described in the above [1],provided that when q-a and t represent an integer of 2 or more, R_(2-a)and R₄ groups may be respectively and independently the same ordifferent;

[6] the compound according to the above [5], wherein R_(2-a) is a 3- to7-membered monocyclic heterocycle;

[7] the compound according to the above [1], wherein the general formula(I) is represented by the general formula (I-iii) or the general formula(I-iv):

wherein R_(2-b) represents the same meaning as R₂; q-b represents aninteger of 0 to 4; and other symbols represent the same meanings asthose described in the above [1] and [5], provided that when q-brepresents an integer of 2 or more, R_(2-b) groups may be respectivelyand independently the same or different;

[8] the compound according to the above [7], wherein R_(2-b) is a 3- to7-membered monocyclic heterocycle;

[9] the compound according to any one of the above [1] to [8], whereinthe ring Cy₁ is a benzene ring or a 5- to 6-membered monocyclic aromaticheterocycle;

[10] the compound according to the above [9], wherein the ring Cy₁ is abenzene ring, a pyridine ring or a pyrazole ring;

[11] a pharmaceutical composition including the compound represented bythe general formula (I) according to the above [1], a salt thereof, anN-oxide thereof, a solvate thereof or a prodrug thereof as an activeingredient;

[12] the composition according to the above [11], which is a Trkinhibitor;

[13] the composition according to the above [11], which is aprophylactic and/or therapeutic agent for Trk-related disease;

[14] the composition according to the above [13], wherein theTrk-related disease is pain, pruritus, lower urinary tract dysfunction,asthma, allergic rhinitis, inflammatory bowel disease or Chagas disease;

[15] the composition according to the above [14], wherein the pain ispain of osteoarthritis, cancer pain, chronic low back pain, low backpain of osteoporosis, pain of bone fracture, pain of rheumatoidarthritis, neuropathic pain, postherpetic pain, pain of diabeticneuropathy, fibromyalgia, pain of pancreatitis, pain of interstitialcystitis, pain of endometriosis, pain of irritable bowel syndrome,migraine, postoperative pain or pain of pulpitis;[16] a medicament which is a combination of the compound represented bythe general formula (I) according to the above [1], a salt thereof, anN-oxide thereof, a solvate thereof or a prodrug thereof and at least oneselected from acetaminophen, a nonsteroid antiinflammatory drug, anopioid, an antidepressant, an antiepileptic agent, anN-methyl-D-aspartate antagonist, a muscle relaxant, an antiarrhythmicagent, a steroid and a bisphosphonate;[17] a method for prophylaxis and/or therapy of Trk-related disease,including administering, to a patient, an effective amount of thecompound represented by the general formula (I) according to the above[1], a salt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof;[18] the compound represented by the general formula (I) according tothe above [1], a salt thereof, an N-oxide thereof, a solvate thereof ora prodrug thereof for prophylaxis and/or therapy of Trk-related disease;[19] a method for inhibiting Trk, including administering, to a patient,an effective amount of the compound represented by the general formula(I) according to the above [1], a salt thereof, an N-oxide thereof, asolvate thereof or a prodrug thereof;[20] use of the compound represented by the general formula (I)according to the above [1], a salt thereof, an N-oxide thereof, asolvate thereof or a prodrug thereof for manufacturing a prophylacticand/or therapeutic agent for Trk-related disease;[21] the compound according to any one of the above [1] to [5], whichis:

-   (1)    1-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea,-   (2)    1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea,-   (3)    1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(5-(trifluoromethyl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)urea,-   (4)    1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-5-(trifluoromethyl)phenyl)urea,-   (5)    1-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)urea,-   (6)    1-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)urea,-   (7)    1-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea,-   (8)    1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea,-   (9)    1-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea,-   (10)    1-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea,-   (11)    1-(2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea,-   (12)    1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea,-   (13)    1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea,-   (14)    1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea,-   (15)    1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-(trifluoromethyl)-2-biphenylyl]urea,-   (16)    1-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-(trifluoromethyl)-2-biphenylyl]urea,-   (17)    1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea,-   (18)    1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{5-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea,-   (19)    1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2,4-bis(trifluoromethyl)phenyl]urea,-   (20)    1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea,-   (21)    1-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea,-   (22)    1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea,-   (23)    1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea    or-   (24)    2-{[(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)carbamoyl]amino}-N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide;    [22] the compound according to any one of the above [1] to [4] and    the above [7], which is:-   (1)    1-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea,-   (2)    1-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea,-   (3)    1-(2-(4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea,-   (4)    1-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea,-   (5)    1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea,-   (6)    1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl]urea,-   (7)    1-{2-[4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea,-   (8)    1-(2-{4-[5-(ethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea,-   (9)    1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[4-(trifluoromethyl)-2-biphenylyl]urea,-   (10)    1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea    or-   (11)    1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea;    [23] an article of manufacture including (1) a pharmaceutical    composition including the compound represented by the general    formula (I) according to the above [1], a salt thereof, an N-oxide    thereof, a solvate thereof or a prodrug thereof, (2) a container    and (3) an instruction, a description, a package insert or a product    label indicating that the composition can be used for prophylaxis    and/or therapy of Trk-related disease;    [24] the article of manufacture according to the above [23], wherein    the Trk-related disease is pain;    [25] an article of manufacture including (1) a pharmaceutical    composition including the compound represented by the general    formula (I) according to the above [1], a salt thereof, an N-oxide    thereof, a solvate thereof or a prodrug thereof, (2) a container    and (3) an instruction, a description, a package insert or a product    label indicating that the composition can be used for prophylaxis    and/or therapy of Trk-related disease in combination with    acetaminophen, a nonsteroid antiinflammatory drug, an opioid, an    antidepressant, an antiepileptic agent, an N-methyl-D-aspartate    antagonist, a muscle relaxant, an antiarrhythmic agent, a steroid    and/or a bisphosphonate;    [26] the article of manufacture according to the above [25], wherein    the Trk-related disease is pain;    [27] an article of manufacture including (1) a pharmaceutical    composition in the form of a combination drug including the compound    represented by the general formula (I) according to the above [1], a    salt thereof, an N-oxide thereof, a solvate thereof or a prodrug    thereof and acetaminophen, a nonsteroid antiinflammatory drug, an    opioid, an antidepressant, an antiepileptic agent, an    N-methyl-D-aspartate antagonist, a muscle relaxant, an    antiarrhythmic agent, a steroid and/or a bisphosphonate, (2) a    container and (3) an instruction, a description, a package insert or    a product label indicating that the composition can be used for    prophylaxis and/or therapy of Trk-related disease; and    [28] the article of manufacture according to the above [27], wherein    the Trk-related disease is pain;

Effect of the Invention

The present compound has Trk-inhibiting activity and excellent kinaseselectivity. Further, the present compound persistently inhibits NGFvascular hyper permeability. Therefore the present compound can be aprophylactic and/or therapeutic agent for Trk-related diseases such aspain, pruritus, lower urinary tract dysfunction, asthma, allergicrhinitis, inflammatory bowel disease or Chagas disease.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is hereinafter specifically described.

In the present invention, “a C3-10 monocyclic carbocycle or bicycliccarbocycle” may include, for example, cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane,cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene,cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene,benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene,perhydroindene, indane, naphthalene, dihydronaphthalene,tetrahydronaphthalene and perhydronaphthalene rings.

In the present invention, “a 4- to 10-membered monocyclic heterocycle orbicyclic heterocycle” in the ring Cy₁ may include, for example, oxetane,azetidine, pyrrolidine, pyrrole, imidazole, triazole, tetrazole,pyrazole, pyridine, piperidine, piperazine, pyrazine, pyrimidine,pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene,thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan,oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole,thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole,indolizine, benzofuran, isobenzofuran, benzothiophene,isobenzothiophene, indazole, quinoline, isoquinoline, quinolidine,purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline,cinnoline, benzoxazole, benzothiazole, benzimidazole, benzodioxole,benzoxathiole, chromene, benzofurazan, benzothiadiazole, benzotriazole,pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline,triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine,dihydropyridine, tetrahydropyridine, dihydropyrazine,tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine,perhydropyrimidine, dihydropyridazine, tetrahydropyridazine,perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine,dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin,tetrahydrooxepin, perhydrooxepin, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine,tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane,dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,dioxolane, dioxane, dioxaindane, benzodioxane, thiochromane,dihydrobenzodioxine, dihydrobenzoxathiine, chromane, pyrazolopyrimidine,imidazopyridazine, imidazopyridine, pyrrolopyridine, imidazopyrazine,pyrazolopyridine, pyrazolopyrimidine, imidazopyridine andtriazolopyridine rings.

In the present invention, “a 4- to 10-membered monocyclic heterocycle orbicyclic heterocycle excluding a heterocycle 1,3-thiazol-5-yl group” inthe ring Cy₂ has the same meaning as “a 4- to 10-membered monocyclicheterocycle or bicyclic heterocycle” in the ring Cy₁ as described above,excluding the heterocycle 1,3-thiazol-5-yl group.

In the present invention, the compound wherein the ring Cy₂ is “a 4- to10-membered monocyclic heterocycle or bicyclic heterocycle excluding aheterocycle 1,3-thiazol-5-yl group” corresponds to the compound of thegeneral formula (I) excluding the compound of the following generalformula (I′):

wherein q′ represents an integer of 0 to 2 and other symbols representthe same meanings as those described in the above [1], provided thatwhen q′ represents 2, R₂ groups may be respectively and independentlythe same or different.

In the present invention, “a halogen” may include fluorine, chlorine,bromine and iodine.

In the present invention, “a C1-6 alkyl group” may include, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,isobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 1-methyl-1-ethylpropyl,2-methyl-2-ethylpropyl, 1-ethylbutyl, 2-ethylbutyl and1,1-dimethylpentyl groups.

In the present invention, “a C2-6 alkenyl group” may include, forexample, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-butenyl,3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,4-hexenyl and 5-hexenyl groups.

In the present invention, “a C2-6 alkynyl group” may include, forexample, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,3-methyl-1-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and5-hexynyl groups.

In the present invention, “a C5-6 monocyclic carbocycle” may include,for example, cyclopentane, cyclohexane, cyclopentene, cyclohexene,cyclopentadiene, cyclohexadiene and benzene rings.

In the present invention, “a 5- to 6-membered monocyclic heterocycle”may include, for example, pyrrole, imidazole, triazole, tetrazole,pyrazole, pyridine, piperidine, piperazine, pyrazine, pyrimidine,pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine,thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,dihydropyrazine, tetrahydropyrazine, dihydropyrimidine,tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholineand oxathiane rings.

In the present invention, “a C1-3 alkyl group” includes methyl, ethyl,n-propyl and isopropyl groups.

In the present invention, “a C3-6 cycloalkyl group” includescyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

In the present invention, “a C1-6 alkoxy group” may include, forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy,tert-butoxy, isobutoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy,3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy,2,2-dimethylpropoxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy,3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 1-methyl-1-ethylpropoxy,1-methyl-2-ethylpropoxy, 1,2-dimethylbutoxy, 2,2-dimethylbutoxy,1-ethyl-2-methylpropoxy, 2-ethyl-2-methylpropoxy and 1-ethylbutoxygroups.

In the present invention, “a 3- to 7-membered monocyclic heterocycle”may include, for example, aziridine, oxetane, azetidine, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, piperidine,piperazine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan,pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyrazine,tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine,perhydropyrimidine, dihydropyridazine, tetrahydropyridazine,perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine,dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin,tetrahydrooxepin, perhydrooxepin, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine,tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine and oxathiane rings.

In the present invention, “a 5- to 10-membered monocyclic aromaticheterocycle or bicyclic aromatic heterocycle excluding a heterocycle1,3-thiazol-5-yl group” may include, for example, pyrrole, imidazole,triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, azepine, diazepine, furan, oxepin, thiophene, thiepine,oxazole, isoxazole, isothiazole, furazan, oxadiazole, oxazepine,oxadiazepine, thiadiazole, indole, isoindole, indolizine, benzofuran,isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline,isoquinoline, quinolidine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, benzofurazan, benzothiadiazole,benzotriazole, pyrazolopyrimidine, imidazopyridazine, imidazopyridine,pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine,imidazopyridine and triazolopyridine rings.

In the present invention, “a 5- to 6-membered monocyclic aromaticheterocycle” may include, for example, pyrrole, imidazole, triazole,tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan,thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan,oxadiazole and thiadiazole rings.

In the present invention, the phrase “when, further, two R₅ groups arerespectively and independently a C1-3 alkyl group or a hydroxy group andthe R₅ groups are attached to carbon atoms adjacent to each other on theC5-6 monocyclic carbocycle or the 5- to 6-membered monocyclicheterocycle, the R₅ groups may together form a ring” may indicate, forexample, the following groups:

wherein a ring Cy₃ represents a C5-6 monocyclic carbocycle or a 5- to6-membered monocyclic heterocycle and an arrow means binding to the ringCy₁.

In the present invention, the phrase “R₅ is —SO₂NR₁₈R₁₉ and when R₁₈ andR₁₉ are respectively and independently a C1-6 alkyl group, R₁₈ and R₁₉may together form a ring” may indicate, for example, the followinggroups:

In the present invention, the ring Cy₁ is preferably a C5-6 monocycliccarbocycle or a 5- to 6-membered monocyclic heterocycle.

In the present invention, the ring Cy₁ is more preferably cyclopentane,cyclohexane, benzene, pyran, thiopyran, pyrrolidine, piperidine,piperazine, imidazoline, imidazolidine, morpholine, thiomorpholine or a5- to 6-membered monocyclic aromatic heterocycle.

In the present invention, the ring Cy₁ is further preferably benzene ora 5- to 6-membered monocyclic aromatic heterocycle.

In the present invention, the ring Cy₁ is still more preferably abenzene, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, furan, thiophene, oxazole, isoxazole, thiazole orisothiazole ring.

In the present invention, the ring Cy₁ is yet more preferably a benzene,imidazole, pyrazole, pyridine, pyrazine, pyrimidine or pyridazine ring.

In the present invention, the ring Cy₁ is yet still more preferably abenzene, pyrazole or pyridine ring.

In the present invention, the ring Cy₁ is the most preferably a benzeneor pyridine ring.

In the present invention, the ring Cy₂ is preferably a 5- to 10-memberedmonocyclic aromatic heterocycle or bicyclic aromatic heterocycleexcluding a heterocycle 1,3-thiazol-5-yl group.

In the present invention, the ring Cy₂ is more preferably a pyridine,pyrazine, pyrimidine, pyridazine, indole, isoindole, indolizine,benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole,quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, benzofurazan, benzothiadiazole,benzotriazole, pyrazolopyrimidine, imidazopyridazine, imidazopyridine,pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine,imidazopyridine or triazolopyridine ring.

In the present invention, the ring Cy₂ is still more preferably apyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole,indolizine, indazole, quinoline, isoquinoline, quinolidine, purine,phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline,cinnoline, benzoxazole, benzothiazole, benzimidazole, benzofurazan,benzothiadiazole, benzotriazole, pyrazolopyrimidine, imidazopyridazine,imidazopyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine,pyrazolopyrimidine, imidazopyridine or triazolopyridine ring.

In the present invention, the ring Cy₂ is yet more preferably apyridine, pyrazine, pyrimidine, pyridazine, pyrazolopyrimidine,imidazopyridazine, imidazopyridine, pyrrolopyridine, imidazopyrazine,pyrazolopyridine, pyrazolopyrimidine, imidazopyridine ortriazolopyridine ring.

In the present invention, the ring Cy₂ is yet still more preferably apyridine, pyrimidine, pyrazolopyrimidine, imidazopyridazine,imidazopyridine, pyrrolopyridine, imidazopyrazine or pyrazolopyridinering.

In the present invention, the ring Cy₂ is the most preferably a pyridineor pyrazolopyrimidine ring.

In the present invention, R₁ is preferably (1) a halogen, (2) a C1-3alkyl group optionally substituted with a halogen, (3) a benzene ringoptionally substituted with one or two R₅ groups, (4) a 5- to 6-memberedmonocyclic aromatic heterocycle optionally substituted with one or twoR₅ groups, (5) a methylsulfonyl group or (6) N,N-dimethylsulfonamide.

In the present invention, R₁ is more preferably (1) a halogen, (2) amethyl group, (3) a trifluoromethyl group, (4) a difluoromethyl group,(5) a monofluoromethyl group, (6) a trichloromethyl group, (7) adichloromethyl group, (8) a monochloromethyl group, (9) a benzene ringoptionally substituted with one or two R₅ groups, (10) a pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole or thiadiazole ring optionallysubstituted with one or two R₅ groups, (11) a methylsulfonyl group or(12) N,N-dimethylsulfonamide.

In the present invention, R₁ is still more preferably (1) a halogen, (2)a methyl group, (3) a trifluoromethyl group, (4) a difluoromethyl group,(5) a monofluoromethyl group, (6) a benzene ring, (7) an indane ring,(8) a tolyl group, (9) a dimethylbenzene ring, (10) an imidazole,triazole, pyrazole or pyridine ring optionally substituted with one ortwo R₅ groups or (11) a methylsulfonyl group.

In the present invention, R₁ is yet more preferably (1) a halogen, (2) atrifluoromethyl group, (3) a difluoromethyl group, (4) a benzene ring,(5) an indane ring, (6) a tolyl group, (7) a dimethylbenzene ring, (8)an imidazole, triazole, pyrazole or pyridine ring optionally substitutedwith one or two methyl, difluoromethyl or trifluoromethyl groups or (9)a methylsulfonyl group.

In the present invention, R₁ is yet still more preferably (1) atrifluoromethyl group, (2) a difluoromethyl group, (3) a benzene ring,(4) a triazole, pyrazole or pyridine ring optionally substituted withone or two methyl, difluoromethyl or trifluoromethyl groups or (5) amethylsulfonyl group.

In the present invention, R₁ is the most preferably (1) atrifluoromethyl group or (2) a triazole, pyrazole or pyridine ringoptionally substituted with one or two methyl, difluoromethyl ortrifluoromethyl groups.

In the present invention, R₅ is preferably (1) a halogen, (2) a methylgroup optionally substituted with a halogen or (3) a C1-3 alkyl groupoptionally substituted with a hydroxy group or an oxo group.

In the present invention, R₅ is more preferably a methyl group, atrifluoromethyl group, a difluoromethyl group, an acetyl group or ahydroxyethyl group.

In the present invention, R₅ is the most preferably a methyl group, atrifluoromethyl group or a difluoromethyl group.

In the present invention, R₂ is preferably (1) a halogen, (2) a C1-3alkyl group optionally substituted with a halogen or a hydroxy group,(3) a C3-6 cycloalkyl group, (4) a C1-3 alkoxy group, (5) an aminogroup, (6) a methylamino, ethylamino, n-propylamino, isopropylamino,n-butylamino, sec-butylamino, tert-butylamino, isobutylamino ordimethylamino group optionally substituted with a hydroxy group, (7) a3- to 7-membered monocyclic heterocycle or (8) —O-(3- to 7-memberedmonocyclic heterocycle).

In the present invention, R₂ is more preferably a halogen, a methylgroup, a trifluoromethyl group, a difluoromethyl group, amonofluoromethyl group, a hydroxymethyl group, a hydroxyethyl group, a2-methyl-hydroxyethyl group, a cyclopropyl group, a methoxy group, anethoxy group, an amino group, a methylamino group, an ethylamino group,a dimethylamino group, a 2-methyl-2-hydroxypropylamino group, anoxetanyloxy group, an azetidine ring, a pyrrolidine ring or a piperidinering.

In the present invention, R₂ is still more preferably a halogen, amethyl group, a cyclopropyl group, a methoxy group, an amino group, adimethylamino group, an oxetanyloxy group, an azetidine ring, apyrrolidine ring or a piperidine ring.

In the present invention, R₂ is yet more preferably a halogen, a methylgroup, an amino group, an azetidine ring or a pyrrolidine ring.

In the present invention, R₂ is the most preferably fluorine, chlorine,a methyl group, an amino group or an azetidine ring.

In the present invention, R₃ is preferably hydrogen or fluorine and themost preferably hydrogen.

In the present invention, R₄ is preferably hydrogen or fluorine and themost preferably hydrogen.

In the present invention, R₆ is preferably a C1-3 alkyl group optionallysubstituted with a halogen.

In the present invention, R₆ is more preferably a methyl group, an ethylgroup or a n-propyl group.

In the present invention, preferably R₇ and R₈ are respectively andindependently a hydrogen atom or a C1-3 alkyl group optionallysubstituted with a hydroxy group.

In the present invention, more preferably R₇ and R₈ are respectively andindependently a hydrogen atom, a methyl group, an ethyl group, an-propyl group, an isopropyl group or a 2-hydroxypropyl group.

In the present invention, still more preferably R₇ and R₈ arerespectively and independently a hydrogen atom, a methyl group, an ethylgroup or a n-propyl group.

In the present invention, R₉ is preferably a hydrogen atom, a methylgroup or an ethyl group.

In the present invention, preferably R₁₀ to R₁₆ are respectively andindependently a hydrogen atom, a methyl group, an ethyl group or an-propyl group.

In the present invention, R₁₇ is preferably a C1-3 alkyl groupoptionally substituted with a halogen.

In the present invention, R₁₇ is more preferably a methyl group, anethyl group or a n-propyl group.

In the present invention, preferably R₁₈ and R₁₉ are respectively andindependently a hydrogen atom or a C1-3 alkyl group optionallysubstituted with a hydroxy group.

In the present invention, more preferably R₁₈ and R₁₉ are respectivelyand independently a hydrogen atom, a methyl group, an ethyl group, an-propyl group, an isopropyl group or a 2-hydroxypropyl group.

In the present invention, still more preferably R₁₈ and R₁₉ arerespectively and independently a hydrogen atom, a methyl group, an ethylgroup or a n-propyl group.

In the present invention, R₂₀ is preferably a hydrogen atom, a methylgroup or an ethyl group.

In the present invention, preferably R₂₁ to R₂₉ are respectively andindependently a hydrogen atom, a methyl group, an ethyl group or an-propyl group.

In the present invention, m1 is preferably an integer of 2.

In the present invention, m2 is preferably an integer of 2.

In the present invention, p is preferably an integer of 0 to 3.

In the present invention, q is preferably an integer of 0 to 3.

In the present invention, r is preferably an integer of 0 to 1.

In the present invention, R_(2-a) and R_(2-b) respectively andindependently have the same meaning as R₂ and preferable groups thereofare also the same as R₂.

In the present invention, q-a is preferably an integer of 0 to 1.

In the present invention, q-b is preferably an integer of 0 to 1.

In the present invention, the general formula (I) is preferably thosehaving the combinations of preferable definitions for the ring Cy₁, thering Cy₂, R₁, R₂, R₃, R₄, R₅, R_(2-a), R_(2-b), m1, m2, p, q, r, t, q-aand q-b.

In the present invention, the general formula (I) is more preferably thegeneral formula (I-a) or the general formula (I-b):

wherein a ring Cy_(2-a) and a ring Cy_(2-b) represent a 5- to10-membered monocyclic aromatic heterocycle or bicyclic aromaticheterocycle excluding a heterocycle 1,3-thiazol-5-yl group, and othersymbols represent the same meanings as those described in [1] and [5]above, a salt thereof, an N-oxide thereof, a solvate thereof or aprodrug thereof.

In the present invention, the general formula (I) is still morepreferably the general formula (I-c) or the general formula (I-d):

wherein a ring Cy_(2-c) and a ring Cy_(2-d) represent a pyridine ring, apyrimidine ring, a pyrazolopyrimidine ring, an imidazopyridazine ring,an imidazopyridine ring, a pyrrolopyridine ring, an imidazopyrazine ringor a pyrazolopyridine ring, and other symbols represent the samemeanings as those described in [1] and [5] above, a salt thereof, anN-oxide thereof, a solvate thereof or a prodrug thereof.

In the present invention, the general formula (I) is yet more preferablythe general formula (I-e) or the general formula (I-f):

wherein a ring Cy_(1-e) and a ring Cy_(1-f) represent a benzene ring ora 5- to 6-membered monocyclic aromatic heterocycle, and other symbolsrepresent the same meanings as those described in [1] and [5] above, asalt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof.

In the present invention, the general formula (I) is yet still morepreferably the general formula (I-g) or the general formula (I-h):

wherein a ring Cy_(1-g) and a ring Cy_(1-h) represent a benzene ring, apyridine ring or a pyrazole ring, and other symbols represent the samemeanings as those described in [1] and [5] above, a salt thereof, anN-oxide thereof, a solvate thereof or a prodrug thereof.

In the present invention, the general formula (I) is yet still morepreferably the general formula (I-j) or the general formula (I-k):

wherein a ring Cy_(2-j) and a ring Cy_(2-k) represent a 5- to10-membered monocyclic aromatic heterocycle or bicyclic aromaticheterocycle excluding a heterocycle 1,3-thiazol-5-yl group; a ringCy_(1-j) and a ring Cy₁-k represent a benzene ring or a 5- to 6-memberedmonocyclic aromatic heterocycle; and other symbols represent the samemeanings as those described in [1] and [5] above, a salt thereof, anN-oxide thereof, a solvate thereof or a prodrug thereof.

In the present invention, the general formula (I) is yet still morepreferably the general formula (I-m) or the general formula (I-n):

wherein a ring Cy_(2-m) and a ring Cy_(2-n) represent a pyridine ring, apyrimidine ring, a pyrazolopyrimidine ring, an imidazopyridazine ring,an imidazopyridine ring, a pyrrolopyridine ring, an imidazopyrazine ringor a pyrazolopyridine ring; a ring Cy_(1-m) and a ring Cy_(1-n)represent a benzene ring, a pyridine ring or a pyrazole ring; and othersymbols represent the same meanings as those described in [1] and [5]above, a salt thereof, an N-oxide thereof, a solvate thereof or aprodrug thereof.

In the present invention, the compound represented by the generalformula (I-n) wherein Cy_(2-n) is a pyrimidine ring is preferably thepresent compound of any of Example 16-1 to Example 16-8 as describedhereinbelow, a salt thereof, an N-oxide thereof, a solvate thereof or aprodrug thereof.

In the present invention, the compound represented by the generalformula (I-m) or the general formula (I-n) wherein the ring Cy_(2-m) orCy_(2-n) is an imidazopyridazine ring is preferably the present compoundof any of Example 22-1 to Example 22-67 as described hereinbelow, a saltthereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

In the present invention, the general formula (I-m) or the generalformula (I-n) is preferably the present compound of any of Example 23-1to Example 23-12 as described hereinbelow, a salt thereof, an N-oxidethereof, a solvate thereof or a prodrug thereof.

In the present invention, the general formula (I) is still morepreferably the general formula (I-i) or the general formula (I-ii):

wherein all symbols represent the same meanings as those described in[1] and [5] above, a salt thereof, an N-oxide thereof, a solvate thereofor a prodrug thereof.

In the present invention, the general formula (I-i) or the generalformula (I-ii) is preferably the general formula (I-i-a) or the generalformula (I-ii-b):

wherein a ring Cy_(1-i-a) and a ring Cy_(1-ii-b) represent a benzenering or a 5- to 6-membered monocyclic aromatic heterocycle and othersymbols represent the same meanings as those described in [1] and [5]above, a salt thereof, an N-oxide thereof, a solvate thereof or aprodrug thereof.

In the present invention, the general formula (I-i) or the generalformula (I-ii) is more preferably the general formula (I-i-c) or thegeneral formula (I-ii-d):

wherein a ring Cy_(1-i-c) and a ring Cy_(1-ii-d) represent a benzenering, a pyridine ring or a pyrazole ring and other symbols represent thesame meanings as those described in [1] and [5] above, a salt thereof,an N-oxide thereof, a solvate thereof or a prodrug thereof.

In the present invention, the general formula (I-i) or the generalformula (I-ii) is the most preferably the present compound of any ofExample 7, Example 8-1 to Example 8-22, Example 9-1 to Example 9-3,Example 11, Example 12, Example 13-1 to Example 13-4, Example 14-1 toExample 14-20 and Example 15-1 to Example 15-251, a salt thereof, anN-oxide thereof, a solvate thereof or a prodrug thereof.

In the present invention, the general formula (I) is still morepreferably the general formula (I-iii) or the general formula (I-iv):

wherein all symbols represent the same meanings as those described in[1], [5] and [7] above, a salt thereof, an N-oxide thereof, a solvatethereof or a prodrug thereof.

In the present invention, the general formula (I-iii) or the generalformula (I-iv) is preferably the general formula (I-iii-a) or thegeneral formula (I-iv-b):

wherein a ring Cy_(1-iii-a) and a ring Cy_(1-iv-b) represent a benzenering or a 5- to 6-membered monocyclic aromatic heterocycle and othersymbols represent the same meanings as those described in [1], [5] and[7] above, a salt thereof, an N-oxide thereof, a solvate thereof or aprodrug thereof.

In the present invention, the general formula (I-iii) or the generalformula (I-iv) is more preferably the general formula (I-iii-c) or thegeneral formula (I-iv-d):

wherein a ring Cy_(1-iii-c) and a ring Cy_(1-iv-d) represent a benzenering or a pyridine ring and other symbols represent the same meanings asthose described in [1], [5] and [7] above, a salt thereof, an N-oxidethereof, a solvate thereof or a prodrug thereof.

In the present invention, the general formula (I-iii) or the generalformula (I-iv) is the most preferably the present compound of any ofExample 20 and Example 21-1 to Example 21-134 as described hereinbelow,a salt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof.

All isomers are encompassed by the present invention unless specificallystated. For example, an alkyl group, an alkenyl group, an alkynyl groupand an alkoxy group comprise linear and branched groups. Further, rings,isomers in fused rings (E, Z, cis and trans forms), isomers due toasymmetric carbons (R and S forms, a and p forms, enantiomers,diastereomers), optically active substances with optical rotatory (D, L,d and l forms), polar substances by chromatographic separation(high-polarity substances, low-polarity substances), equilibratedcompounds, rotational isomers, mixtures thereof with any proportions andracemic mixtures are all encompassed by the present invention.

Isomers due to tautomeric properties are also encompassed by the presentinvention.

In the present invention, as is apparent to the one skilled in the art,unless otherwise stated the symbol:

indicates that the bond projects below the plane of the paper (i.e.α-configuration), the symbol:

indicates that the bond projects above the plane of the paper (i.e.β-configuration), the symbol:

indicates that the bond is the α-configuration or the β-configuration,and the symbol:

indicates that the bond is a mixture of the α-configuration and theβ-configuration with any proportions.

[Salts]

The compound represented by the general formula (I) may be converted toa salt according to well known methods.

The salt is preferably a pharmaceutically acceptable salt.

The salt is preferably water soluble.

The salt may include, for example, acid addition salts, alkali metalsalts, alkaline-earth metal salts, ammonium salts and amine salts.

The acid addition salt may include, for example, inorganic acid saltssuch as hydrochlorides, hydrobromides, hydroiodides, sulfates,phosphates and nitrates and organic acid salts such as acetates,lactates, tartrates, benzoates, citrates, methanesulfonates,ethanesulfonates, trifluoroacetates, benzenesulfonates,toluenesulfonates, isethionates, glucuronates and gluconates.

The alkali metal salt may include, for example, potassium and sodium.

The alkaline-earth metal salt may include, for example, calcium andmagnesium.

The ammonium salt may include, for example, tetramethylammonium.

The amine salt may include, for example, triethylamine, methylamine,dimethylamine, cyclopentylamine, benzylamine, phenethylamine,piperidine, monoethanolamine, diethanolamine,tris(hydroxymethyl)aminomethane, lysine, arginine andN-methyl-D-glucamine.

The present compound may be converted to an N-oxide according to anymethods. The N-oxide represents the compound of the general formula (I)in which a nitrogen atom thereof is oxidized and specifically may be thecompound represented by the general formula (I) wherein the nitrogenatom in A₁, A₂, A₃, A₄, As or A₆, which is ═N—, is oxidized.Alternatively, the N-oxide may be the compound represented by thegeneral formula (I) wherein the nitrogen atom in Cy₁ and Cy₂, which area nitrogen-containing heterocycle, is oxidized. Further, the N-oxide maybe the compound represented by the general formula (I) wherein an aminogroup is oxidized.

The compound represented by the general formula (I) and a salt thereofmay be converted to a solvate.

The solvate is preferably non-toxic and water soluble. Appropriatesolvates may include, for example, solvates with water or an alcoholicsolvent (e.g., ethanol).

[Prodrugs]

A prodrug of the compound represented by the general formula (I) refersto a compound that is converted to the compound represented by thegeneral formula (I) by in vivo reaction with an enzyme or gastric acid.The prodrug of the compound represented by the general formula (I) mayinclude, for example, compounds wherein an amino group in the compoundrepresented by the general formula (I) is acylated, alkylated orphosphated (e.g., compounds wherein an amino group in the compoundrepresented by the general formula (I) is derivatized to eicosanoyl,alanyl, pentylaminocarbonyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl,pyrrolidylmethyl, pivaloyloxymethyl, acetoxymethyl or tert-butyl);compounds wherein a hydroxy group in the compound represented by thegeneral formula (I) is acylated, alkylated, phosphated or borated (e.g.,compounds wherein a hydroxy group in the compound represented by thegeneral formula (I) is derivatized to acetyl, palmitoyl, propanoyl,pivaloyl, succinyl, fumaryl, alanyl or dimethylaminomethylcarbonyl);compounds wherein a carboxy group in the compound represented by thegeneral formula (I) is esterified or amidated (e.g., compounds wherein acarboxy group in the compound represented by the general formula (I) isderivatized to ethyl ester, phenyl ester, carboxymethyl ester,dimethylaminomethyl ester, pivaloyloxymethyl ester,1-{(ethoxycarbonyl)oxy}ethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,1-{[(cyclohexyloxy)carbonyl]oxy}ethyl ester or methylamide) and thelike. These compounds may be prepared according to the methods wellknown per se. The prodrug of the compound represented by the generalformula (I) may be a hydrate or non-hydrate. The prodrug of the compoundrepresented by the general formula (I) may be the one which is convertedto the compound represented by the general formula (I) underphysiological conditions described in “Iyakuhin no Kaihatsu (Developmentof Medicines)”, vol. 7, “Bunshi Sekkei (Molecular Designs)”, HirokawaShoten Co., 1990, pp. 163-198.

The atoms constituting the compound represented by the general formula(I) may respectively be substituted with isotopes thereof (e.g., ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁶N, ¹⁷O, ¹⁸O, ³⁵S, ³⁶C1, ⁷⁷Br, ¹²⁵I and the like).

Production Method of the Present Compound

The present compound represented by the general formula (I) can beproduced according to well known methods, for example the methodsdescribed hereinbelow, equivalent methods thereof or methods describedin Examples. In the production methods described hereinbelow, startingcompounds may be salts. The salts may include those described aspharmaceutically acceptable salts of the general formula (I).

The present compound of the general formula (I) can be prepared, forexample, according to the following reaction scheme:

wherein X₁ represents a boronic acid group (—B(OH)₂) or a boronate estergroup (—B(ORi)(ORii), wherein Ri and Rii represent a C1-3 alkyl groupand Ri and Rii may together form a ring, such as4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl); X₂ represents a halogen;X₃ represents a halogen; and other symbols represent the same meaningsas those described in the above [1].

The present compound having an amino group, an ester group and a hydroxygroup can be produced by carrying out the reactions up to ureaderivatization reaction as indicated in the above reaction scheme with acompound which may be optionally protected with a protecting groupconventionally used for the above-mentioned groups as described in, forexample, “Comprehensive Organic Transformations: A Guide to FunctionalGroup Preparations 2nd Edition (Richard C. Larock, John Wiley & SonsInc, 1999)” followed by a well known deprotection reaction or thedeprotection reaction described in, for example, “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations 2nd Edition(Richard C. Larock, John Wiley & Sons Inc, 1999)”.

In the reaction scheme, the reaction step (carbamate derivatizationreaction) of producing the compound represented by the general formula(III) from the compound represented by the general formula (II) is wellknown. The compound represented by the general formula (III) obtainedthereby can be produced by, for example, allowing reaction of thecompound represented by the general formula (II) with2,2,2-trichloroethoxycarbonyl chloride in an organic solvent (e.g.,pyridine, ethyl acetate, methylene chloride, dioxane, diethyl ether oran appropriately mixed solvent thereof) or in a mixed solvent of theorganic solvent with water in the presence or absence of a base (e.g.,4-dimethylaminopyridine, pyridine, triethylamine, sodium hydrogencarbonate) at a temperature of about −20° C. to 80° C.

In the reaction scheme, the reaction step (etherification reaction,reduction reaction) of producing the compound represented by the generalformula (VI) from the compound represented by the general formula (IV)is well known. The compound represented by the general formula (VI)obtained thereby can be produced by, for example, allowing reaction ofthe compound represented by the general formula (IV) and the compoundrepresented by the general formula (V) in an organic solvent (e.g.,dimethylsulfoxide, dimethylformamide, methanol, acetonitrile,tetrahydrofuran or an appropriately mixed solvent thereof) or in a mixedsolvent of the organic solvent with water in the presence of a base(e.g., potassium fluoride, potassium carbonate, tripotassium phosphate,sodium hydroxide, sodium hydride, triethylamine) at a temperature ofabout 0° C. to 120° C. and subjecting the obtained compound to reactionunder a hydrogen atmosphere in an organic solvent (e.g., methanol,ethanol, ethyl acetate, tetrahydrofuran, acetic acid,1,2-dimethoxyethane or an appropriately mixed solvent thereof) or in amixed solvent of the organic solvent with water in the presence of acatalyst (e.g., a silver catalyst (e.g., silver acetate), a platinumcatalyst (e.g., platinum-carbon, platinum oxide), a rhodium catalyst(e.g., rhodium-carbon), an iron catalyst (e.g., iron acetate), aruthenium catalyst (e.g., ruthenium-carbon), a palladium catalyst (e.g.,palladium-carbon, palladium hydroxide), a zinc catalyst (zinc bromide,zinc iodide, zinc acetate), Raney nickel or an appropriately mixedcatalyst thereof) at a temperature of from room temperature to about 80°C. or subjecting to reaction in an organic solvent (e.g., acetic acid,hydrochloric acid, ethanol, methanol, dimethylformamide, toluene or anappropriately mixed solvent thereof) or in a mixed solvent of theorganic solvent with water in the presence of a catalyst (e.g., an ironcatalyst (e.g., iron, iron chloride, iron-ammonium chloride), a zinccatalyst (e.g., zinc), a nickel catalyst (e.g., nickel chloride), anindium catalyst (e.g., indium), a tin catalyst (e.g., tin, tin chloride)or an appropriately mixed catalyst thereof) at a temperature of fromroom temperature to about 80° C.

In the reaction scheme, the reaction step (aryl derivatization reaction)of producing the compound represented by the general formula (VIII) fromthe compound represented by the general formula (VI) is well known. Thecompound represented by the general formula (VIII) obtained thereby canbe produced by, for example, allowing reaction of the compoundrepresented by the general formula (VI) and the compound represented bythe general formula (VII) in an organic solvent (e.g.,dimethylacetamide, dimethylformamide, an alcohol (e.g., methanol,ethanol, isopropyl alcohol), diethyl carbonate, dioxane,1,2-dimethoxyethane, toluene or an appropriately mixed solvent thereof)or in a mixed solvent of the organic solvent with water, in the presenceor absence of a base (e.g., caesium carbonate, potassium acetate,potassium carbonate, sodium carbonate, lithium-t-butoxide, silvercarbonate, tripotassium phosphate, triethylamine or an appropriatelymixed base thereof) in a catalyst (e.g., a palladium catalyst (e.g.,palladium hydroxide, palladium acetate,bis(tri-t-butylphosphine)palladium, palladium(0)tetrakis(triphenylphosphine), bis(triphenylphosphine)dichloropalladium(II) or an appropriately mixed catalyst thereof)) at a temperature offrom room temperature to about 120° C.

In the reaction scheme, the reaction step (urea derivatization reaction)of producing the present compound represented by the general formula (I)from the compound represented by the general formula (VIII) is thereaction carried out with the compound represented by the generalformula (VIII) and the compound represented by the general formula (III)or general formula (IX) under the conditions described in Examplesherein or under well known conditions.

In the reaction scheme, compounds used as starting materials andrepresented by the general formulae (II), (IV), (V), (VI) and (IX) arewell known or can be easily produced according to well known methods,for example, the method described in “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations 2nd Edition(Richard C. Larock, John Wiley & Sons Inc, 1999)”.

The present compound of the general formula (I) can be alternativelyproduced by subjecting to urea derivatization reaction the compoundrepresented by the general formula (II) and a 2,2,2-trichloroethylcarbamate derivative produced from the compound represented by thegeneral formula (VIII) in the above reaction scheme and2,2,2-trichloroethoxycarbonyl chloride.

The present compounds represented by the general formula (I) other thanthose indicated above can be produced according to the methods describedin Examples herein or to the combinations of well known methods, forexample, the method described in “Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock,John Wiley & Sons Inc, 1999)”.

The respective reactions involving heating as described herein can becarried out, as apparent to a person skilled in the art, in a waterbath, an oil bath, a sand bath or with microwave.

In the respective reactions as described herein, a reagent supported ona solid phase of a high-molecular weight polymer (e.g., polystyrene,polyacrylamide, polypropylene, polyethylene glycol) may be appropriatelyused.

In the respective reactions as described herein, reaction products canbe purified by conventional purification means, e.g., by methodsincluding distillation under normal or reduced pressure, high speedliquid chromatography using silica gel or magnesium silicate, thin layerchromatography, ion exchange resins, scavenger resins or columnchromatography or washing and recrystallization. Purification may becarried out after each reaction step or may be carried out after morethan one reaction steps.

[Toxicity]

The present compound has sufficiently low toxicity. The present compounddoes not cause, for example, hepatotoxicity or gastrointestinaldysfunction and has low brain transition. Thus the present compound canbe used safely as a medicament.

[Application to Medicaments]

The present compound exhibits Trk-inhibiting activity and thus is usefulas a prophylactic and/or therapeutic agent for Trk-related diseasese.g., pain, pruritus, lower urinary tract dysfunction, asthma, allergicrhinitis, inflammatory bowel disease and Chagas disease.

More specifically, pain may include, for example, pain ofosteoarthritis, cancer pain, chronic low back pain, low back pain ofosteoporosis, pain of bone fracture, pain of rheumatoid arthritis,neuropathic pain, postherpetic pain, pain of diabetic neuropathy,fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, painof endometriosis, pain of irritable bowel syndrome, migraine,postoperative pain, pain of pulpitis and the like. Pruritus may includesystemic cutaneous pruritus, localized cutaneous pruritus, senilecutaneous pruritus, gestational pruritus, pruritus ani, vulvar pruritusand the like. Inflammatory bowel disease may include, for example,ulcerative colitis, Crohn's disease and the like.

The present compound is particularly useful as a prophylactic and/ortherapeutic agent for pain.

The present compound may be administered as a combination drug withanother drug in order to:

1) complement and/or enhance the prophylactic and/or therapeutic effectof the compound;

2) improve the kinetics and absorption and reduce the dosage of thecompound; and/or

3) alleviate the side effect of the compound.

The combination drug of the present compound and another drug may beadministered in the form of one formulation containing both componentsor may be administered as separate formulations. Administration ofseparate formulations may include simultaneous administration andsequential administration. In the sequential administration, the presentcompound may be first administered followed by another drug or anotherdrug may be first administered followed by the present compound. Therespective manners of administration may be the same or different.

The disease for which the combination drug exhibits the prophylacticand/or therapeutic effect is not particularly limited and may be thedisease which may complement and/or enhance the prophylactic and/ortherapeutic effect of the present compound.

Another drug for complementing and/or enhancing the prophylactic and/ortherapeutic effect of the present compound for pain may include, forexample, acetaminophen, a nonsteroid antiinflammatory drug, an opioid,an antidepressant, an antiepileptic agent, an N-methyl-D-aspartateantagonist, a muscle relaxant, an antiarrhythmic agent, a steroid and abisphosphonate.

The nonsteroid antiinflammatory drug may include, for example,sasapyrine, sodium salicylate, aspirin, aspirin formulations such asthose containing aspirin-dialuminate, diflunisal, indomethacin,suprofen, ufenamate, dimethylisopropylazulene, bufexamac, felbinac,diclofenac, tolmetin sodium, Clinoril, fenbufen, nabumetone,proglumetacin, indomethacin farnesil, acemetacin, proglumetacin maleate,amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol,naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, fenoprofencalcium, Tiaprofen, oxaprozin, pranoprofen, loxoprofen sodium,alminoprofen, zaltoprofen, mefenamic acid, aluminium mefenamate,tolfenamic acid, floctafenine, ketophenylbutazone, oxyphenbutazone,piroxicam, tenoxicam, ampiroxicam, Napageln ointment, epirizole,tiaramide hydrochloride, tinoridine hydrochloride, emorfazone,sulpyrine, Migrenin, Saridon, Sedes G, Amipylo-N, Sorbon, pilin coldremedies, acetaminophen, phenacetin, dimetotiazine mesilate, meloxicam,celecoxib, rofecoxib, valdecoxib, simetride-containing formulations andnon-pilin cold remedies and the like.

The opioid may include, for example, codeine, fentanyl, hydromorphone,levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone,propoxyphene and the like.

The antidepressant may include, for example, tricyclic antidepressants(e.g., amitriptyline hydrochloride, imipramine hydrochloride,clomipramine hydrochloride, dosulepin hydrochloride, nortriptylinehydrochloride, lofepramine hydrochloride, trimipramine maleate,amoxapine), tetracyclic antidepressants (e.g., maprotilinehydrochloride, mianserin hydrochloride, setiptiline maleate), monoamineoxidase (MAO) inhibitors (safrazine hydrochloride), serotonin andnoradrenaline reuptake inhibitors (SNRIs) (e.g., milnacipranhydrochloride, venlafaxine hydrochloride), selective serotonin reuptakeinhibitors (SSRIs) (e.g., fluvoxamine maleate, paroxetine hydrochloride,fluoxetine hydrochloride, citalopram hydrochloride), serotonin reuptakeinhibitors (e.g., trazodone hydrochloride) and the like.

The antiepileptic agent may include, for example, phenobarbital,Puridomin, phenytoin, ethosuximide, zonisamide, nitrazepam, clonazepam,carbamazepine, sodium valproate, acetazolamide, sulthiame and the like.

The N-methyl-D-aspartate antagonist may include, for example, ketaminehydrochloride, amantadine hydrochloride, memantine hydrochloride,dextromethorphan, methadone and the like.

The muscle relaxant may include, for example, succinylcholine,suxamethonium, vecuronium bromide, pancronium bromide, dantrolene sodiumand the like.

The antiarrhythmic agent may include, for example, procainamide,disopyramide, cibenzoline, pirmenol, lidocaine, mexiletine, aprindine,pilsicainide, flecainide, propafenone, propranolol, atenolol,bisoprolol, amiodarone, sotalol, verapamil, diltiazem, bepridil and thelike.

The steroid may include, for example, as external medicines, clobetasolpropionate, diflorasone diacetate, fluocinonide, mometasone furoate,betamethasone dipropionate, betamethasone butyrate propionate,betamethasone valerate, difluprednate, budesonide, diflucortolonevalerate, amcinonide, halcinonide, dexamethasone, dexamethasonepropionate, dexamethasone valerate, dexamethasone acetate,hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyratepropionate, deprodone propionate, prednisolone valerate acetate,fluocinolone acetonide, peclometasone propionate, triamcinoloneacetonide, flumethasone pivalate, alclometasone dipropionate,clobetasone butyrate, prednisolone, beclomethasone propionate,fludroxycortide and the like.

As medicines for internal use or for injection, cortisone acetate,hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodiumsuccinate, fludrocortisone acetate, prednisolone, prednisolone acetate,prednisolone sodium succinate, prednisolone butylacetate, prednisolonesodium phosphate, halopredone acetate, methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate,triamcinolone, triamcinolone acetate, triamcinolone acetonide,dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate,dexamethasone palmitate, paramethasone acetate, betamethasone and thelike may be included.

As inhalants, beclomethasone propionate, fluticasone propionate,budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide,dexamethasone palmitate, mometasone furoate, prasterone sulfonate,deflazacort, methylprednisolone suleptanate, methylprednisolone sodiumsuccinate and the like may be included.

The bisphosphonate may include, for example, etidronate, pamidronate,alendronate, risedronate, zoledronate, minodronate and the like.

The mass ratio of the present compound and another drugs is notparticularly limited.

Any combination of two or more kinds of another drugs may beadministered.

Another drugs for complementing and/or enhancing the prophylactic and/ortherapeutic effect of the present compound may encompass not only thosehave been identified to date but also those will be identified in futurebased on the above mechanism.

The present compound or the combination drug of the present compound andanother drugs which is used for the purpose described above is generallyformulated as an appropriate pharmaceutical composition with apharmaceutically acceptable carrier, and then administered systemicallyor topically by oral or parenteral administration.

The dosage may vary according to age, weight, symptoms, therapeuticeffect, mode of administration, treatment period and the like and may beone to several oral administrations a day within the range of 1 mg to1000 mg per dose per adult or one to several parenteral administrationsa day within the range of 0.1 mg to 100 mg per dose or intravenouscontinuous administration for 1 hour to 24 hours a day per adult.

As described above, the dosage may vary according to various conditions,thus the sufficient dosage may be of course lower than the amountdescribed above or the amount higher than the above may be required.

The present compound or the combination drug of the present compound andanother drugs may be administered as an oral solid dosage form forinternal use, an internal liquid medicine or an injection, an externalmedicine, a suppository, an ophthalmic solution or an inhalation forparenteral administration.

The oral solid dosage form for internal use may include tablets, pills,capsules, powders, granules and the like. Capsules may include hardcapsules and soft capsules. Tablets may include sublingual tablets, oralpatches, orally disintegrating tablets and the like.

In the solid dosage form for internal use, one or more active substancesper se may be formulated or may be formulated after mixing thereof witha excipient (lactose, mannitol, glucose, microcrystalline cellulose,starch and the like), a binder (hydroxypropylcellulose,polyvinylpyrrolidone, magnesium aluminate metasilicate and the like), adisintegrant (calcium cellulose glycolate and the like), a lubricant(magnesium stearate and the like), a stabilizer, a solution adjuvant(glutamic acid, aspartic acid and the like) according to conventionalmethods. The solid dosage form may be optionally coated with a coatingagent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate and the like) and may be coated with two ormore layers. The solid dosage form may further encompass capsules of anabsorbable substance such as gelatin.

The internal liquid medicine may include pharmaceutically acceptablewaters, suspensions, emulsions, syrups, elixirs and the like. In theliquid medicine, one or more active substances are dissolved, suspendedor emulsified in a diluent of general use (purified water, ethanol or amixed solution thereof). The liquid medicine may further contain awetting agent, a suspending agent, an emulsifying agent, a sweeteningagent, a flavouring agent, an aroma, a preservative, a buffering agentand the like.

The dosage form of the external medicine for parenteral administrationmay include, for example, ointments, gels, creams, cataplasms, plastersand pressure sensitive adhesives, liniments, atomized agents,inhalations, sprays, aerosols, ophthalmic solutions, nasal solutions andthe like. The dosage forms contain one or more active substances and maybe prepared according to well known methods or formulations which aregenerally used.

Atomized agents, inhalations and sprays may contain, in addition to adiluent which is generally used, a stabilizer such as sodium hydrogensulfite and a buffering agent that confers isotonicity, e.g., sodiumchloride, sodium citrate or an isotonicity agent such as citric acid.Methods for producing sprays are specifically described in, for example,U.S. Pat. No. 2,868,691 and U.S. Pat. No. 3,095,355.

The injection for parenteral administration may encompass injections inthe form of solution, suspension, emulsion and solid that is dissolvedor suspended in a solvent upon use. The injection may be used bydissolving, suspending or emulsifying one or more active substances in asolvent. The solvent may be, for example, distilled water for injection,saline, vegetable oil, propylene glycol, polyethylene glycol, alcoholssuch as ethanol and combinations thereof. The injection may furthercontain a stabilizer, a solution adjuvant (glutamic acid, aspartic acid,Polysorbate 80® and the like), a suspending agent, an emulsifying agent,a soothing agent, a buffering agent, a preservative and the like. Theinjection may be produced by sterilization in the final step or throughaseptic technique. Aseptic solid agents, e.g., lyophilized products maybe manufactured and dissolved in sterilized or aseptic distilled wateror other solvents for injection before use.

Other compositions for parenteral administration may includesuppositories for rectal administration and pessaries for vaginaladministration which contain one or more active substances and areformulated according to conventional methods.

In the present invention, “an article of manufacture” comprises (1) apharmaceutical composition including the present compound or apharmaceutical composition in the form of a combination drug includingthe present compound with a concomitant drug other than the presentcompound, (2) a container containing the composition and (3) at leastone of an instruction, a description, a package insert and a productlabel (including those corresponding to a label and a labeling in theUnited States), all of which indicate that the composition can be usedfor prophylaxis and/or therapy of Trk-related disease optionally incombination with an appropriate concomitant drug (preferablyacetaminophen, a nonsteroid antiinflammatory drug, an opioid, anantidepressant, an antiepileptic agent, an N-methyl-D-aspartateantagonist, a muscle relaxant, an antiarrhythmic agent, a steroid and/ora bisphosphonate).

The package insert as used herein means an official document attached toa medicament which provides necessary information for appropriate use ofthe medicament and corresponds to “Tenpu Bunsho” (also referred to as“Nou-gaki”) in accordance with the Pharmaceutical Affairs Act in Japan,“Summary of Product Characteristics (SPC or SmPC)” in accordance withDirective in EU, “US Package Insert (USPI)” in accordance with FederalRegulations in the United States and equivalent documents elsewhere.

The information provided by these documents is specifically prescribedby Articles 52, 54 and 68 (4) and the like in the Pharmaceutical AffairsAct (see, if necessary, Notification Nos. 606 and 607 of PharmaceuticalAffairs Bureau as of 25 Apr. 1997 and/or related notifications) for“Tenpu Bunsho” in Japan, by Directive 2001/83/EC Article 11 and the like(see, if necessary, A guideline on SmPC and/or related guidelines) forSummary of Product Characteristics in EU, and by 21 CFR201.100 and thelike (see, if necessary, 21 CFR 201.57 and/or related FederalRegulations) for US Package Insert in the United States and generallyincludes information on indications, dosage and administration, methodof administration, warnings and/or contraindications.

In the United States, 21 CFR 201 Subpart B requires that in addition tothe US Package Insert, a label or a labeling (or labelling) shouldcontain a part or all information provided on the US Package Insert. Alabel herein means the one directly provided on a container and alabeling means the concept encompassing the label, printing on packagesand printed matters attached to articles of manufacture.

In the present invention, the term “container” means the one whichdirectly accommodates the pharmaceutical composition comprising thepresent compound or the pharmaceutical composition in the form of acombination drug including the present compound with a concomitant drugother than the present compound and may also be referred to as “animmediate container”, “an immediate wrapper”, “an inner seal” or thelike. The container includes, for example, cans/tins, bottles, boxes,ampoules, vials, tubes, unit dose containers for eye drops, paper,cloth, plastics, plastic bags, SP sheets, PTP sheets, plastic containersand the like.

The container containing the pharmaceutical composition therein iscombined with at least one of an instruction, a description, a packageinsert and a product label (including the one corresponding to a labelor labeling in the United Stated) as described above, and then may begenerally packaged in an outer container or an outer wrapper anddistributed to the market.

The present invention also discloses a method for advertisement of apharmaceutical composition comprising the present compound or apharmaceutical composition in the form of a combination drug includingthe present compound with a concomitant drug, the method includingencouraging a target viewer to use the composition for prophylaxisand/or therapy of Trk-related disease.

The above method involves publicly distributing information thatdescribes the value, particularly a health benefit of using, inprophylaxis and/or therapy for Trk-related diseases, the pharmaceuticalcomposition including the present compound or the pharmaceuticalcomposition in the form of the combination drug including the presentcompound with another concomitant drug. Such information is distributedthrough an appropriate advertising medium in addition to verbalcommunication. The advertising medium may be any of newspaper,magazines, television, radio, video, brochures, leaflets, posters,social networking systems, e-mail, electronic signboards, digitalsignage, internet advertisements (homepages/websites, banneradvertisements and the like), outdoor advertisements (poster boards,neon signs, large screen displays and the like), transportationadvertisements (advertisements suspended in trains, buses, cabs and thelike, advertisements above windows and beside doors of trains, buses,cabs and the like, advertisements in stations), movie theatre slideadvertisements (advertisements on screens in movie theatres), POPadvertisements (advertisements at shop front and in shops), directadvertisements (direct mails, newspaper inserts, flyers), specialtyadvertisements (novelty advertisements such as calendars, pens and thelike), other advertisements (skywriting, advertisements on benches andthe like). A person skilled in the art can easily produce theadvertising media.

Unless otherwise defined, all technical and scientific terms andabbreviations used herein have the same meanings as are usuallyunderstood by a person skilled in the art to which the present inventionpertains.

The present application claims the priority of Japanese PatentApplication Nos. 2013-029563 and 2013-141246 filed respectively on 19Feb. 2013 and 5 Jul. 2013, the entire contents of which are incorporatedherein by reference.

The contents of all Patent Document and Non-Patent Document orreferences explicitly cited herein may be entirely incorporated hereinas a part of the present specification.

EXAMPLES

The present invention is hereinafter specifically described by way ofExamples which do not limit the present invention.

The solvents indicated in brackets described in chromatographicseparation and TLC sections indicate elution solvents or developmentsolvents used and the proportions are expressed in volume ratio.

The solvents indicates in brackets described in NMR sections indicatethe solvents used for measurements.

LC-MS/ELSD was carried out under the following conditions:

{Column: Waters ACQUITY C₁₈ (particle diameter: 1.7×10⁻⁶ m; columnlength: 30×2.1 mm I.D.); flow rate: 1.0 mL/min; column temperature: 40°C.; mobile phase (A): 0.1% trifluoroacetic acid aqueous solution; mobilephase (B): 0.1% trifluoroacetic acid-acetonitrile solution; gradient(the ratio of mobile phase (A):mobile phase (B)): [0 min] 95:5; [0.1min] 95:5; [1.2 min] 5:95; [1.4 min] 5:95; [1.41 min]95:5; [1.5 min]95:5; detector: UV(PDA), ELSD, MS}

The compounds described herein were named by using a computer programmegenerally according to IUPAC nomenclature system, ACD/Name®, or ChemdrawUltra (version 12.0, Cambridge Soft), or according to IUPAC nomenclaturesystem.

Example 1 1-(2-nitro-4-(trifluoromethyl)phenyl)-1H-pyrazole

To a solution of 1H-pyrazole (0.39 g) in dimethylsulfoxide (hereinafterabbreviated as DMSO) (5.2 mL) was added potassium tert-butoxide (0.7 g).The reaction mixture was stirred at room temperature for 40 minutes. Tothe reaction mixture was gradually added1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.1 g) and the reactionmixture was further stirred for 90 minutes. The reaction mixture waspoured with a saturated ammonium chloride aqueous solution and extractedwith ethyl acetate. The obtained organic layer was washed with water anda saturated sodium chloride aqueous solution, dried over magnesiumsulfate and then concentrated under reduced pressure. The obtainedresidue was purified on silica gel column chromatography (hexane:ethylacetate=10:1→2:1) to give the titled compound having the followingphysical characteristics (0.43 g).

TLC:Rf 0.43 (Hexane:Ethyl Acetate=3:1);

¹H-NMR (DMSO-d₆): δ 6.61-6.64 (m, 1H), 7.82 (d, 1H), 8.07 (d, 1H), 8.20(dd, 1H), 8.45-8.49 (m, 2H).

Example 2 2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline

To a solution of the compound produced in Example 1 (430 mg) in methanol(16 mL) was added palladium-carbon (5% wet, 380 mg). The reactionmixture was placed in a hydrogen atmosphere and stirred at roomtemperature for 6 hours. The reaction mixture was filtered throughCelite (trade name) followed by concentration of the filtrate to givethe titled compound having the following physical characteristics (357mg).

TLC:Rf 0.56 (Hexane:Ethyl Acetate=3:1);

¹H-NMR (DMSO-d₆): δ 6.10 (s, 2H), 6.52-6.56 (m, 1H), 6.92 (dd, 1H), 7.19(d, 1H), 7.45 (d, 1H), 7.79 (d, 1H), 8.21 (d, 1H).

Example 32,2,2-trichloroethyl(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)carbamate

To a solution of the compound produced in Example 2 (356 mg) in ethylacetate (8 mL) were added sodium hydrogen carbonate (400 mg) and2,2,2-trichloroethyl carbonochloridate (430 mg). The reaction mixturewas stirred at room temperature for 150 minutes. The reaction mixturewas added with water and extracted with ethyl acetate. The obtainedorganic layer was dried over magnesium sulfate and then concentratedunder reduced pressure. The obtained residue was purified on silica gelcolumn chromatography (hexane:ethyl acetate=10:1→2:1) to give the titledcompound having the following physical characteristics (610 mg).

TLC:Rf 0.60 (Hexane:Ethyl Acetate=3:1);

¹H-NMR (DMSO-d₆): δ 4.93 (s, 2H), 6.63-6.66 (m, 1H), 7.66 (dd, 1H), 7.88(d, 1H), 7.94 (d, 1H), 8.29 (s, 1H), 8.42 (d, 1H), 10.6 (s, 1H).

Example 45-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine

To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol(10 g) in tetrahydrofuran (hereinafter abbreviated as THF) (91 mL) wereadded triethylamine (7 mL) and 2-chloro-5-nitropyrimidine (7.6 g). Thereaction mixture was stirred at 0° C. for 1 hour. The reaction mixturewas diluted in ethyl acetate and washed with a saturated sodium hydrogencarbonate aqueous solution, water and a saturated sodium chlorideaqueous solution. The obtained organic layer was dried over sodiumsulfate and then concentrated under reduced pressure to give the titledcompound having the following physical characteristics (17 g).

TLC:Rf 0.45 (Hexane:Ethyl Acetate=4:1);

¹H-NMR (CDCl₃): δ 1.35 (s, 12H), 7.20 (d, 2H), 7.93 (d, 2H), 9.31 (s,2H).

Example 52-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidin-5-amine

To a solution of the compound produced in Example 4 (17 g) in a mixtureof ethanol (187 mL) and ethyl acetate (94 mL) was added palladiumhydroxide (20% wet, 1.56 g). The reaction mixture was stirred in ahydrogen atmosphere at 35° C. for 4 hours. The reaction mixture wasadded with methanol (90 mL) and activated carbon (0.32 g) and stirred atroom temperature for 5 minutes. The reaction mixture was filteredthrough Celite (trade name) followed by concentration of the filtrate.To the obtained residue was added an 1:1 mixed solvent of tert-butylmethyl ether/hexane and the precipitated solid was filtered to give thetitled compound having the following physical characteristics (12.8 g).

TLC:Rf 0.29 (Hexane:Ethyl Acetate=1:1);

¹H-NMR (CDCl₃): δ 1.33 (s, 12H), 3.51 (br s, 2H), 7.14 (d, 2H), 7.85 (d,2H), 8.06 (s, 2H).

Example 6 2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-amine

To a solution of the compound produced in Example 5 (1 g) in a mixtureof 2-propanol (6.4 mL) and 1,2-dimethoxyethane (1.6 mL) were added3-bromo-5-chloropyridin-2-amine (662 mg), potassium phosphate aqueoussolution (2 M, 3.2 mL) and bis(triphenylphosphinepalladium)dichloride(112 mg). The reaction mixture was stirred in an argon atmosphere at 85°C. for 2 hours. The reaction mixture was cooled to room temperature,diluted in ethyl acetate and then washed with water. The obtainedorganic layer was back extracted with hydrochloric acid (0.5 M, 120 mL).The obtained aqueous layer was neutralized with a saturated sodiumcarbonate aqueous solution and extracted with ethyl acetate. Theobtained organic layer was washed with a saturated sodium chlorideaqueous solution, dried over sodium sulfate and then filtered. Theobtained organic layer was concentrated to around 100 mL. Theconcentrated solution was purified on column chromatography (FujiSilysia Chromatorex NH DM1020 (trade name), ethyl acetate) to give thetitled compound having the following physical characteristics (857 mg).

TLC:Rf 0.32 (Dichloromethane:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 5.28 (br s, 2H), 5.82 (br s, 2H), 7.14 (d, 2H), 7.39(d, 1H), 7.45 (d, 2H), 7.94 (d, 1H), 7.99 (s, 2H).

Example 71-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea

To a solution of the compound produced in Example 6 (400 mg) and thecompound produced in Example 3 (513 mg) in N,N-dimethylacetamide(hereinafter abbreviated as DMA) (2.6 mL) was added triethylamine (0.018mL). In an argon atmosphere, the reaction mixture was stirred at 65° C.for 21 hours. The reaction mixture was cooled to room temperature andthen diluted in ethyl acetate. The obtained organic layer was washedthree times with water and once with a saturated sodium chloride aqueoussolution. The obtained organic layer was dried over sodium sulfate,filtered and then concentrated. The obtained residue was purified onsilica gel column chromatography (dichloromethane:ethyl acetate=2:1) togive the present compound having the following physical characteristics(465 mg).

TLC:Rf 0.29 (Hexane:Ethyl Acetate=1:3);

¹H-NMR (DMSO-d₆): δ 5.86 (br s, 2H), 6.68 (dd, 1H), 7.27 (d, 2H), 7.42(d, 1H), 7.46-7.56 (m, 3H), 7.75 (d, 1H), 7.92-7.99 (m, 2H), 8.41 (d,1H), 8.58 (d, 1H), 8.70 (s, 2H), 9.71 (br s, 1H), 9.97 (br s, 1H).

Example 8

The similar procedure as Example 7 was carried out with a correspondingcarbamate or isocyanate compound in place of the compound produced inExample 3 to give the present compounds having the following physicalcharacteristics.

Example 8-11-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.21 (Hexane:Ethyl Acetate=1:3);

¹H-NMR (DMSO-d₆): δ 2.38 (s, 3H), 5.85 (s, 2H), 7.26 (d, 2H), 7.41 (d,1H), 7.50 (d, 2H), 7.58 (dd, 1H), 7.69 (d, 1H), 7.94 (d, 1H), 8.39 (s,1H), 8.58-8.61 (m, 1H), 8.68 (s, 2H), 8.76 (s, 1H), 9.69 (s, 1H).

Example 8-21-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(5-(trifluoromethyl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)urea

TLC:Rf 0.80 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.12 (d, 1H), 7.26 (s, 2H), 7.42 (s,1H), 7.51 (d, 2H), 7.58 (dd, 1H), 7.71 (d, 1H), 7.95 (d, 1H), 8.47 (s,2H), 8.59 (s, 1H), 8.67 (s, 2H), 9.48 (s, 1H).

Example 8-31-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.69 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.84 (s, 2H), 7.26 (d, 2H), 7.41 (d, 1H), 7.51 (d,2H), 7.61 (dd, 1H), 7.74 (d, 1H), 7.95 (d, 1H), 8.09 (d, 1H), 8.57 (s,1H), 8.67 (s, 3H), 8.71 (s, 1H), 9.65 (s, 1H).

Example 8-41-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.52 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.26 (d, 2H), 7.41 (d, 1H), 7.51 (d,2H), 7.68 (dd, 1H), 7.86-7.89 (m, 1H), 7.94 (d, 1H), 8.42 (s, 1H), 8.74(s, 2H), 8.79 (s, 1H), 9.76 (s, 1H).

Example 8-51-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(5-(trifluoromethyl)-2-(4-trifluoromethyl)-1H-pyrazol-1-yl)phenyl)urea

TLC:Rf 0.36 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.26 (d, 2H), 7.42 (d, 1H), 7.50 (d,2H), 7.56 (dd, 1H), 7.76 (d, 1H), 7.95 (d, 1H), 8.38 (s, 1H), 8.54-8.59(m, 1H), 8.69 (s, 2H), 8.98 (d, 2H), 9.75 (s, 1H).

Example 8-61-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(3-(difluoromethyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.27 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 6.90-6.96 (m, 1H), 7.14 (t, 1H), 7.26(d, 2H), 7.41 (d, 1H), 7.50 (d, 2H), 7.53-7.59 (m, 1H), 7.72 (d, 1H),7.95 (d, 1H), 8.41-8.46 (m, 1H), 8.53 (s, 1H), 8.68 (s, 2H), 8.95 (s,1H), 9.66 (s, 1H).

Example 8-71-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(5-(trifluoromethyl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)urea

TLC:Rf 0.62 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.26 (d, 2H), 7.42 (d, 1H), 7.50 (d,2H), 7.63 (dd, 1H), 7.81 (d, 1H), 7.95 (d, 1H), 8.47-8.50 (m, 1H), 8.65(s, 1H), 8.66 (s, 2H), 9.24 (s, 1H), 9.33 (s, 1H).

Example 8-81-(2-(3-acetyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.34 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.58 (s, 3H), 5.85 (s, 2H), 7.05 (d, 1H), 7.26 (d,2H), 7.42 (d, 1H), 7.50 (d, 2H), 7.57 (dd, 1H), 7.74 (d, 1H), 7.95 (d,1H), 8.39 (d, 1H), 8.63 (s, 1H), 8.68 (s, 2H), 8.74 (s, 1H), 9.63 (s,1H).

Example 8-91-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.50 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 2.37 (s, 3H), 5.85 (s, 2H), 6.45 (d, 1H), 7.27 (d,2H), 7.43 (d, 1H), 7.47-7.54 (m, 3H), 7.70 (d, 1H), 7.95 (d, 1H), 8.28(d, 1H), 8.57 (s, 1H), 8.70 (s, 2H), 9.81 (s, 1H), 9.92 (s, 1H).

Example 8-101-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.47 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 7.27-7.34 (m, 3H), 7.42-7.53 (m, 4H), 7.61-7.66 (m,1H), 7.88-7.92 (m, 2H), 8.73 (s, 2H).

Example 8-111-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.50 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.26 (d, 2H), 7.38-7.55 (m, 5H), 7.95(d, 1H), 8.51-8.55 (m, 1H), 8.74 (s, 2H), 9.09 (s, 1H), 9.30 (s, 1H).

Example 8-121-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.55 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 2.15 (s, 3H), 5.85 (s, 2H), 7.26 (d, 2H), 7.42 (d,1H), 7.49-7.52 (m, 3H), 7.69 (d, 1H), 7.78 (s, 1H), 7.95 (d, 1H), 8.18(d, 1H), 8.57 (d, 1H), 8.70 (d, 2H), 9.83 (s, 1H), 9.97 (s, 1H).

Example 8-131-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(5-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.63 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.19 (s, 3H), 5.84 (d, 2H), 7.26 (d, 2H), 7.42 (d,2H), 7.50 (d, 2H), 7.61 (d, 1H), 7.84 (s, 1H), 7.94 (d, 1H), 8.29 (s,1H), 8.64 (s, 1H), 8.66 (s, 2H), 9.45 (s, 1H).

Example 8-141-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-methyl-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.30 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 2.32 (s, 3H), 5.85 (s, 2H), 7.28 (d, 2H), 7.31 (d,1H), 7.39-7.44 (m, 2H), 7.51 (d, 2H), 7.95 (d, 1H), 8.27 (s, 1H), 8.38(s, 1H), 8.75 (s, 2H), 9.34 (s, 1H).

Example 8-151-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(3-(1-hydroxyethyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.19 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 1.44 (d, 3H), 4.92 (quint., 1H), 5.23 (d, 1H), 5.85(s, 2H), 6.58 (d, 1H), 7.26 (d, 2H), 7.42 (d, 1H), 7.47-7.54 (m, 3H),7.72 (d, 1H), 7.95 (d, 1H), 8.28-8.31 (m, 1H), 8.50 (d, 1H), 8.69 (s,2H), 9.69 (s, 1H), 9.85 (s, 1H).

Example 8-161-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.46 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.26 (d, 2H), 7.42 (d, 1H), 7.50 (d,2H), 7.59 (d, 1H), 7.77 (d, 1H), 7.95 (d, 1H), 8.42 (s, 1H), 8.56 (s,1H), 8.68 (s, 2H), 8.79 (s, 1H), 9.09 (s, 1H), 9.66 (s, 1H).

Example 8-171-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.80 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.36 (d, 3H), 5.85 (s, 2H), 7.26 (dd, 2H), 7.34 (d,1H), 7.42 (d, 1H), 7.51 (dd, 2H), 7.57 (d, 1H), 7.89 (d, 1H), 7.96 (d,1H), 8.72 (s, 2H), 8.92 (s, 1H), 9.18 (s, 1H).

Example 8-181-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.26 (Ethyl Acetate:Hexane=1:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.26 (d, 1H), 7.27 (dd, 2H), 7.43 (d,1H), 7.51 (dd, 2H), 7.53-7.65 (m, 2H), 7.70 (s, 1H), 7.95 (d, 1H), 8.73(s, 2H), 9.11 (s, 1H), 9.52 (s, 1H).

Example 8-191-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.53 (Ethyl Acetate:Hexane=3:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.25 (dd, 2H), 7.42 (dd, 1H), 7.51 (d,2H), 7.61 (d, 1H), 7.70 (d, 1H), 7.95 (dd, 1H), 8.06 (s, 1H), 8.72 (s,2H), 9.04 (s, 1H), 9.44 (s, 1H).

Example 8-201-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(5-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.39 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 2.20 (s, 3H), 5.84 (s, 2H), 6.40 (s, 1H), 7.26 (d,2H), 7.41 (d, 1H), 7.52 (d, 2H), 7.53 (d, 1H), 7.55 (d, 1H), 7.75 (d,1H), 7.94 (d, 1H), 8.40 (s, 1H), 8.61 (s, 1H), 8.67 (s, 2H), 9.73 (s,1H).

Example 8-211-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.28 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.19 (s, 3H), 5.85 (s, 2H), 6.88 (s, 1H), 7.26 (d,2H), 7.38-7.43 (m, 1H), 7.46-7.63 (m, 4H), 7.92-7.97 (m, 1H), 8.31 (s,1H), 8.61 (s, 1H), 8.67 (s, 2H), 9.38 (s, 1H).

Example 8-221-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-chloro-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.80 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.27 (d, 2H), 7.43 (s, 2H), 7.51 (d,2H), 7.84 (s, 2H), 7.95 (d, 1H), 8.73 (s, 2H), 9.15 (s, 1H), 9.51 (s,1H).

Example 9

The similar procedures as Example 4→Example 5→Example 6→Example 7 werecarried out with 3-bromo-5-chloropyridin-2-amine or3-bromo-5-fluoropyridin-2-amine in place of3-bromo-5-chloropyridin-2-amine; 2-chloro-5-nitropyridine in place of2-chloro-5-nitropyrimidine; and the compound produced in Example 3 or acorresponding carbamate compound in place of the compound produced inExample 3 to give the present compounds having the following physicalcharacteristics.

Example 9-11-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)urea

TLC:Rf 0.62 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 6.67 (t, 1H), 7.04 (d, 1H), 7.15 (d,2H), 7.39 (d, 1H), 7.45-7.51 (m, 3H), 7.72 (d, 1H), 7.93-7.94 (m, 2H),8.00 (dd, 1H), 8.19 (d, 1H), 8.39 (d, 1H), 8.58 (d, 1H), 9.56 (s, 1H),9.82 (s, 1H).

Example 9-21-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)urea

TLC:Rf 0.69 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.84 (s, 2H), 7.04 (d, 1H), 7.16 (d, 2H), 7.39 (d,1H), 7.47 (d, 2H), 7.59 (d, 1H), 7.72 (d, 1H), 7.94 (d, 1H), 7.99 (dd,1H), 8.10 (d, 1H), 8.15 (d, 1H), 8.59-8.61 (m, 2H), 8.68 (s, 1H), 9.57(s, 1H).

Example 9-31-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyridin-3-yl)urea

TLC:Rf 0.27 (Hexane:Ethyl Acetate=1:3);

¹H-NMR (DMSO-d₆): δ 5.55 (s, 2H), 6.67 (t, 1H), 7.04 (d, 1H), 7.16 (d,2H), 7.34 (dd, 1H), 7.47-7.50 (m, 3H), 7.72 (d, 1H), 7.91-7.94 (m, 2H),8.01 (dd, 1H), 8.19 (d, 1H), 8.39 (d, 1H), 8.59 (d, 1H), 9.55 (s, 1H),9.82 (s, 1H).

Example 10 2-(pyridin-3-yl)-5-(trifluoromethyl)aniline

To a solution of 2-bromo-5-(trifluoromethyl)aniline (10 g) and3-pyridineboronic acid (5.63 g) in acetonitrile (20 mL) were added water(10 mL), sodium carbonate (14.57 g) and bis(triphenylphosphine)palladium(II) dichloride (1.46 g). In an argon atmosphere, the reaction mixturewas stirred at 100° C. for 14 hours. The reaction mixture was cooled toroom temperature and extracted with ethyl acetate. The organic layer wasdried over magnesium sulfate and then concentrated under reducedpressure. The obtained residue was purified on silica gel columnchromatography (hexane:ethyl acetate=1:0→0:1), washed with hexane andthen dried to give the titled compound having the following physicalcharacteristics (7.62 g).

TLC:Rf 0.56 (Ethyl Acetate:Hexane=3:1);

¹H-NMR (DMSO-d₆): δ 5.40 (s, 2H), 6.90 (d, 1H), 7.08 (s, 1H), 7.18 (d,1H), 7.48 (dd, 1H), 7.85 (d, 1H), 8.57 (d, 1H), 8.60 (d, 1H).

Example 111-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

The similar procedures as Example 3→Example 4→Example 5→Example6→Example 7 were carried out with 2-chloro-5-nitropyridine in place of2-chloro-5-nitropyrimidine and the compound produced in Example 10 inplace of the compound produced in Example 2 to give the present compoundhaving the following physical characteristics.

TLC:Rf 0.43 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.80 (s, 2H), 7.04 (d, 1H), 7.16 (s, 2H), 7.41 (d,1H), 7.47 (s, 1H), 7.50 (s, 2H), 7.54-7.61 (m, 2H), 7.90 (dt, 1H), 7.91(d, 1H), 7.99 (s, 1H), 8.11-8.15 (m, 2H), 8.43 (s, 1H), 8.64-8.71 (m,2H), 9.20 (s, 1H).

Example 121-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

The similar procedures as Example 3→Example 7 were carried out with thecompound produced in Example 10 in place of the compound produced inExample 2 to give the present compound having the following physicalcharacteristics.

TLC:Rf 0.60 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 5.84 (s, 2H), 7.25 (d, 2H), 7.41 (d, 1H), 7.48-7.58(m, 5H), 7.89 (dd, 1H), 7.94 (d, 1H), 8.23 (s, 1H), 8.38 (s, 1H),8.65-8.68 (m, 4H), 9.23 (s, 1H)

Example 13

The similar procedures as Example 10→Example 3→Example 7 were carriedout with a corresponding boronic acid compound or a boronate estercompound in place of 3-pyridineboronic acid to give the presentcompounds having the following physical characteristics.

Example 13-11-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.60 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 3.65 (s, 3H), 5.85 (s, 2H), 6.46 (s, 1H), 7.27 (d,2H), 7.42 (d, 1H), 7.50-7.52 (m, 4H), 7.62 (s, 1H), 7.95 (d, 1H), 8.09(s, 1H), 8.56 (s, 1H), 8.68 (s, 2H), 9.49 (s, 1H).

Example 13-21-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.40 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 3.92 (s, 3H), 5.85 (s, 2H), 7.25-7.27 (m, 2H),7.39-7.42 (m, 2H), 7.49-7.51 (m, 3H), 7.76 (s, 1H), 7.95 (d, 1H), 8.10(s, 1H), 8.24-8.27 (m, 2H), 8.71 (s, 2H), 9.41 (s, 1H).

Example 13-31-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.78 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 3.73 (s, 3H), 5.85 (s, 2H), 6.96 (s, 1H), 7.26 (d,2H), 7.42 (d, 1H), 7.51 (d, 2H), 7.53 (d, 1H), 7.58 (d, 1H), 7.95 (d,1H), 8.28 (s, 1H), 8.53 (s, 1H), 8.68 (s, 2H), 9.32 (s, 1H).

Example 13-41-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.48 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 8.57 (s, 2H), 6.92 (d, 1H), 7.28 (d,2H), 7.39 (d, 1H), 7.43 (d, 1H), 7.52 (d, 2H), 7.94 (dd, 3H), 8.65 (s,1H), 8.74 (s, 2H), 9.93 (s, 1H), 10.77 (s, 1H).

Example 14

The similar procedures as Example 6→Example 7 were carried out with3-bromo-5-fluoropyridin-2-amine in place of3-bromo-5-chloropyridin-2-amine; and Example 3 or a correspondingcarbamate or isocyanate compound in place of Example 3 to give thepresent compounds having the following physical characteristics.

Example 14-11-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.65 (Hexane:Ethyl Acetate=1:9);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.28 (d, 2H), 7.35-7.54 (m, 5H), 7.93(d, 1H), 8.51-8.53 (m, 1H), 8.74 (s, 2H), 9.09 (s, 1H), 9.29 (s, 1H).

Example 14-21-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.16 (Ethyl Acetate:Hexane=1:1);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.27 (d, 2H), 7.33 (d, 1H), 7.38 (dd,1H), 7.51 (d, 1H), 7.53 (dd, 2H), 7.60 (d, 1H), 7.94 (d, 1H), 7.97 (s,1H), 8.73 (s, 2H), 8.98 (s, 1H), 9.431 (s, 1H).

Example 14-31-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(5-(trifluoromethyl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)urea

TLC:Rf 0.74 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.12 (d, 1H), 7.27 (d, 2H), 7.37 (dd,1H), 7.53 (d, 2H), 7.59 (dd, 1H), 7.71 (d, 1H), 7.94 (d, 1H), 8.47 (s,2H), 8.58 (s, 1H), 8.67 (s, 2H), 9.48 (s, 1H).

Example 14-41-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.49 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 6.68 (s, 1H), 7.27 (d, 2H), 7.38 (dd,1H), 7.53 (d, 3H), 7.75 (d, 1H), 7.92-7.98 (m, 2H), 8.41 (s, 1H), 8.58(s, 1H), 8.70 (s, 2H), 9.70 (s, 1H), 9.96 (s, 1H).

Example 14-51-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.69 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.55 (s, 2H), 7.27 (d, 2H), 7.37 (dd, 1H), 7.52 (d,2H), 7.61 (d, 1H), 7.74 (d, 1H), 7.93 (d, 1H), 8.09 (s, 1H), 8.57 (s,1H), 8.67 (s, 3H), 8.71 (s, 1H), 9.65 (s, 1H).

Example 14-61-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.62 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 5.55 (s, 2H), 7.25 (d, 2H), 7.36 (dd, 1H), 7.48-7.58(m, 5H), 7.89 (dd, 1H), 7.93 (d, 1H), 8.24 (s, 1H), 8.38 (s, 1H),8.64-8.68 (m, 4H), 9.23 (s, 1H).

Example 14-71-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.33 (Ethyl Acetate:Hexane=3:1);

¹H-NMR (DMSO-d₆): δ 2.38 (s, 3H), 5.56 (s, 2H), 7.26 (d, 2H), 7.36 (dd,1H), 7.52 (dd, 2H), 7.60 (d, 1H), 7.69 (d, 1H), 7.94 (d, 1H), 8.34 (s,1H), 8.59 (d, 1H), 8.68 (d, 2H), 8.76 (s, 1H), 9.69 (s, 1H).

Example 14-81-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.31 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 3.92 (s, 3H), 5.56 (s, 2H), 7.27 (d, 2H), 7.35-7.42(m, 2H), 7.51-7.55 (m, 3H), 7.76 (s, 1H), 7.93 (d, 1H), 8.10 (s, 1H),8.24 (s, 1H), 8.28 (s, 1H), 8.71 (s, 2H), 9.42 (s, 1H).

Example 14-91-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.50 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 3.65 (s, 3H), 5.56 (s, 2H), 6.45 (s, 1H), 7.27 (d,2H), 7.37 (dd, 1H), 7.49-7.54 (m, 4H), 7.62 (s, 1H), 7.94 (d, 1H), 8.09(s, 1H), 8.56 (s, 1H), 8.68 (s, 2H), 9.49 (s, 1H).

Example 14-101-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.44 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.27 (d, 2H), 7.36 (dd, 1H), 7.51 (d,2H), 7.57 (d, 1H), 7.77 (d, 1H), 7.93 (d, 1H), 8.41 (s, 1H), 8.56 (d,1H), 8.68 (s, 2H), 8.78 (s, 1H), 9.09 (s, 1H), 9.66 (s, 1H).

Example 14-111-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-methyl-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.38 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 2.32 (s, 3H), 5.56 (s, 2H), 7.25-7.46 (m, 5H), 7.54(d, 2H), 7.94 (d, 1H), 8.27 (s, 1H), 8.38 (s, 1H), 8.75 (s, 2H), 9.33(s, 1H).

Example 14-121-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.71 (Hexane:Ethyl Acetate=1:9);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.28 (d, 2H), 7.36-7.41 (m, 2H), 7.53(d, 2H), 7.72 (d, 1H), 7.93 (d, 1H), 8.56 (s, 1H), 8.74 (s, 2H), 8.78(s, 1H), 9.71 (s, 1H).

Example 14-131-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.50 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 2.15 (s, 3H), 5.56 (s, 2H), 7.26 (d, 2H), 7.36 (dd,1H), 7.47-7.55 (m, 3H), 7.70 (d, 1H), 7.78 (s, 1H), 7.93 (d, 1H), 8.18(s, 1H), 8.57 (d, 1H), 8.70 (s, 2H), 9.83 (s, 1H), 9.96 (s, 1H).

Example 14-141-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(5-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.63 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.20 (s, 3H), 5.55 (s, 2H), 7.27 (d, 2H), 7.37 (dd,1H), 7.53 (d, 2H), 7.62 (d , 2H), 7.84 (s, 1H), 7.94 (d, 1H), 8.30 (s,1H), 8.65 (s, 1H), 8.67 (s, 2H), 9.46 (s, 1H).

Example 14-151-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.43 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 2.36 (s, 3H), 5.57 (s, 2H), 7.27 (d, 2H), 7.30-7.42(m, 2H), 7.50-7.60 (m, 3H), 7.89 (s, 1H), 7.94 (d, 1H), 8.72 (s, 2H),8.92 (s, 1H), 9.18 (s, 1H).

Example 14-161-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.45 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 2.37 (s, 3H), 5.56 (s, 2H), 6.45 (s, 1H), 7.28 (d,2H), 7.38 (dd, 1H), 7.48-7.60 (m, 1H), 7.53 (d, 2H), 7.70 (d, 1H), 7.94(d, 1H), 8.28 (d, 1H), 8.57 (s, 1H), 8.70 (s, 2H), 9.81 (s, 1H), 9.92(s, 1H).

Example 14-171-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.20 (Ethyl Acetate:Hexane=1:1);

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 7.22-7.33 (m, 3H), 7.38 (dd, 1H), 7.53(d, 2H), 7.62 (d, 1H), 7.72 (s, 1H), 7.94 (d, 1H), 8.73 (s, 2H), 9.11(s, 1H), 9.52 (s, 1H).

Example 14-181-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.46 (Ethyl Acetate:Hexane=3:1);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.26 (d, 2H), 7.38 (dd, 1H), 7.52 (d,2H), 7.61 (d, 1H), 7.68 (d, 1H), 7.93 (dd, 1H), 8.07 (s, 1H), 8.72 (d,2H), 9.05 (s, 1H), 9.44 (s, 1H).

Example 14-191-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-chloro-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.80 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 7.27 (dd, 2H), 7.36 (dd, 1H), 7.43 (s,1H), 7.53 (dd, 2H), 7.83 (d, 2H), 7.93 (s, 1H), 8.73 (s, 2H), 9.13 (s,1H), 9.49 (s, 1H).

Example 14-201-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(5-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.39 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 2.20 (s, 3H), 5.50 (s, 2H), 6.40 (s, 1H), 7.27 (d,2H), 7.37 (dd, 1H), 7.51-7.55 (m, 4H), 7.75 (s, 1H), 7.93 (d, 1H), 8.40(s, 1H), 8.61 (s, 1H), 8.67 (s, 2H), 9.73 (s, 1H).

Example 15

The similar procedures as Example 4→Example 5→Example 6→Example 7 werecarried out with 3-bromo-5-chloropyridin-2-amine or a correspondingamine compound in place of 3-bromo-5-chloropyridin-2-amine;2-chloro-5-nitropyrimidine or 2-chloro-5-nitropyridine in place of2-chloro-5-nitropyrimidine; and a corresponding carbamate or isocyanatecompound in place of the compound produced in Example 3 to give thepresent compounds having the following physical characteristics.

Example 15-11-(2-(4-(2-amino-5-methylpyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.22 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 2.16 (s, 3H), 5.47 (s, 2H), 7.21-7.27 (m, 3H), 7.33(d, 1H), 7.47-7.54 (m, 3H), 7.62 (d, 1H), 7.79 (s, 1H), 7.97 (s, 1H),8.73 (s, 2H), 8.99 (s, 1H), 9.32 (s, 1H).

Example 15-21-(2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.54 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 6.66 (d, 1H), 7.27 (d, 2H), 7.36 (dd,1H), 7.52 (dd, 2H), 7.75 (d, 1H), 7.83 (s, 1H), 7.94 (d, 2H), 8.42-8.44(m, 2H), 8.70 (s, 2H), 9.57 (s, 1H), 9.97 (s, 1H).

Example 15-31-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.37 (Dichloromethane:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.29 (d, 2H), 7.38 (dd, 1H), 7.50-7.55(m, 2H), 7.69 (dd, 1H), 7.89 (d, 1H), 7.94 (d, 1H), 8.43 (d, 1H), 8.75(s, 2H), 8.80 (s, 1H), 9.77 (s, 1H).

Example 15-41-(2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.40 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.83 (s, 2H), 6.67 (t, 1H), 7.28 (d, 2H), 7.43 (d,1H), 7.52 (d, 2H), 7.74-7.77 (m, 1H), 7.84 (s, 1H), 7.94-7.97 (m, 2H),8.43-8.45 (m, 2H), 8.72 (s, 2H), 9.57 (s, 1H), 9.96 (s, 1H).

Example 15-51-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.45 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.84 (s, 2H), 7.27 (d, 2H), 7.43 (d, 1H), 7.46-7.55(m, 3H), 7.67 (d, 1H), 7.96 (d, 1H), 8.38 (t, 1H), 8.75 (s, 2H), 9.24(br, 2H).

Example 15-61-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.45 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.28 (d, 2H), 7.43 (d, 1H), 7.52 (d,2H), 7.69 (dd, 1H), 7.89 (d, 1H), 7.96 (d, 1H), 8.42 (d, 1H), 8.75 (s,2H), 8.80 (s, 1H), 9.77 (s, 1H).

Example 15-71-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,4-dichlorophenyl)urea

TLC:Rf 0.59 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.27 (d, 2H), 7.41 (dd, 1H), 7.42 (d,1H), 7.50 (d, 2H), 7.63 (d, 1H), 7.95 (d, 1H), 8.14 (d, 1H), 8.57 (s,1H), 8.72 (s, 2H), 9.59 (s, 1H).

Example 15-81-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,4-dichlorophenyl)urea

TLC:Rf 0.50 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.27 (d, 2H), 7.35-7.43 (m, 2H), 7.51(d, 2H), 7.63 (d, 1H), 7.93 (d, 1H), 8.14 (d, 1H), 8.57 (s, 1H), 8.72(s, 2H), 9.59 (s, 1H).

Example 15-91-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,4,5-trifluorophenyl)urea

TLC:Rf 0.40 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.28 (d, 2H), 7.38 (dd, 1H), 7.53 (d,2H), 7.62-7.66 (m, 1H), 7.94 (d, 1H), 8.08-8.15 (m, 1H), 8.73 (s, 2H),8.93 (s, 1H), 9.21 (s, 1H).

Example 15-101-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,4-difluorophenyl)urea

TLC:Rf 0.45 (Ethyl Acetate:Hexane=3:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.04 (t, 1H), 7.26 (d, 2H), 7.31 (dd,1H), 7.42 (d, 1H), 7.51 (d, 2H), 7.94-8.04 (m, 2H), 8.71-8.72 (m, 3H),9.16 (s, 1H).

Example 15-111-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,5-dichlorophenyl)urea

TLC:Rf 0.56 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.12 (dd, 1H), 7.26 (d, 2H), 7.42 (d,1H), 7.49-7.55 (m, 3H), 7.95-7.97 (m, 1H), 8.26 (d, 1H), 8.64 (s, 1H),8.74 (d, 2H), 9.68 (s, 1H).

Example 15-121-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,5-difluorophenyl)urea

TLC:Rf 0.54 (Ethyl Acetate:Hexane=3:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 6.84 (m, 1H), 7.26-7.32 (m, 3H), 7.42(d, 1H), 7.51 (dd, 2H), 7.93-8.01 (m, 2H), 8.73 (s, 2H), 8.96 (s, 1H),9.27 (s, 1H).

Example 15-131-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(difluoromethyl)phenyl)urea

TLC:Rf 0.34 (Dichloromethane:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.00 (t, 1H), 7.17 (d, 1H), 7.25-7.29(m, 2H), 7.39-7.45 (m, 2H), 7.49-7.53 (m, 3H), 7.78 (s, 1H), 7.95 (d,1H), 8.73 (s, 2H), 8.91 (s, 1H), 9.17 (s, 1H).

Example 15-141-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(4-fluorophenyl)urea

TLC:Rf 0.50 (Ethyl Acetate:Hexane=3:1);

¹H-NMR (DMSO-d₆): δ 5.84 (s, 2H), 7.06-7.13 (m, 2H), 7.25 (d, 2H), 7.42(d, 1H), 7.46-7.51 (m, 4H), 7.94 (d, 1H), 8.71 (d, 2H), 9.40 (br, 2H).

Example 15-151-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,5-dichlorophenyl)urea

TLC:Rf 0.50 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.12 (dd, 1H), 7.28 (d, 2H), 7.37 (dd,1H), 7.49 (d, 1H), 7.53 (d, 2H), 7.94 (d, 1H), 8.25 (d, 1H), 8.64 (s,1H), 8.73 (s, 2H), 9.68 (s, 1H).

Example 15-161-(2-(4-(2-aminopyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.47 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 6.66 (t, 1H), 7.24 (d, 2H), 7.34 (d,1H), 7.46-7.58 (m, 6H), 7.89 (d, 1H), 7.94 (d, 1H), 8.24 (s, 1H), 8.38(s, 1H), 8.65-8.68 (m, 3H), 9.24 (s, 1H).

Example 15-171-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3,4-difluorophenyl)urea

TLC:Rf 0.79 (Ethyl Acetate:Hexane=3:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.13-7.16 (m, 1H), 7.26 (d, 2H),7.30-7.40 (m, 1H), 7.42 (d, 1H), 7.51 (d, 2H), 7.59-7.67 (m, 1H), 7.95(d, 1H), 8.71 (s, 2H), 8.93 (s, 1H), 9.16 (s, 1H).

Example 15-181-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(3-methyl-1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.23 (Hexane:Ethyl Acetate=1:1);

¹H-NMR (DMSO-d₆): δ 2.36 (s, 3H), 5.85 (s, 2H), 6.43 (d, 1H), 7.27 (d,2H), 7.42 (d, 1H), 7.50 (d, 2H), 7.70 (d, 1H), 7.76 (s, 1H), 7.95 (d,1H), 8.29 (d, 1H), 8.40 (d, 1H), 8.70 (s, 2H), 9.63 (s, 1H), 9.92 (s,1H).

Example 15-191-(2-(4-(2-amino-5-cyclopropylpyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.54 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 0.59-0.64 (m, 2H), 0.81-0.87 (m, 2H), 1.77-1.86 (m,1H), 5.36 (s, 2H), 7.01 (d, 1H), 7.25 (d, 2H), 7.32 (d, 1H), 7.47-7.54(m, 3H), 7.62 (d, 1H), 7.80 (d, 1H), 7.97 (s, 1H), 8.72 (s, 2H), 8.99(s, 1H), 9.32 (s, 1H).

Example 15-201-(2-(4-(2-amino-5-methylpyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.53 (Ethyl Acetate:Methanol:Aqueous Ammonia=9:1);

¹H-NMR (DMSO-d₆): δ 2.15 (s, 3H), 5.34 (s, 2H), 7.20-7.24 (m, 3H),7.46-7.58 (m, 5H), 7.78 (s, 1H), 7.87-7.90 (m, 1H), 8.24 (s, 1H), 8.38(s, 1H), 8.64-8.68 (m, 4H), 9.24 (s, 1H).

Example 15-211-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.51 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.84 (s, 2H), 7.26 (d, 2H), 7.42 (d, 1H), 7.51-7.56(m, 5H), 7.76 (d, 1H), 7.90 (d, 1H), 7.95 (d, 1H), 8.24 (s, 1H), 8.27(d, 1H), 8.66-8.68 (m, 2H), 9.28 (s, 1H).

Example 15-221-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(difluoromethyl)phenyl)urea

TLC:Rf 0.33 (Dichloromethane:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 7.00 (t, 1H), 7.17 (d, 1H), 7.26-7.29(m, 2H), 7.36-7.45 (m, 2H), 7.51-7.55 (m, 3H), 7.78 (s, 1H), 7.94 (d,1H), 8.73 (s, 2H), 8.91 (s, 1H), 9.17 (s, 1H).

Example 15-231-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.82 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.27 (d, 2H), 7.42 (d, 1H), 7.51 (d,2H), 7.64 (d, 4H), 7.95 (d, 1H), 8.73 (s, 2H), 8.98 (s, 1H), 9.37 (s,1H).

Example 15-241-(2-(4-(2-aminopyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.20 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 5.58 (s, 2H), 6.60 (dd, 1H), 7.25-7.37 (m, 4H),7.47-7.63 (m, 4H), 7.94-7.97 (m, 2H), 8.73 (s, 2H), 9.00 (s, 1H), 9.33(s, 1H).

Example 15-251-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(4-(trifluoromethyl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-phenyl)urea

TLC:Rf 0.39 (Hexane:Ethyl Acetate=1:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.11 (d, 1H), 7.26 (d, 2H), 7.42 (d,1H), 7.50 (d, 2H), 7.81 (s, 1H), 7.85-7.88 (m, 1H), 7.95 (d, 1H), 8.36(d, 1H), 8.47 (s, 1H), 8.53 (s, 1H), 8.67 (s, 2H), 9.50 (s, 1H).

Example 15-261-(2-(4-(2-aminopyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(3,4-dimethylphenyl)-5-(trifluoromethyl)pyridin-3-yl)urea

TLC:Rf 0.29 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 2.31 (s, 6H), 5.57 (s, 2H), 6.66 (dd, 1H), 7.25 (d,2H), 7.31-7.42 (m, 4H), 7.48 (d, 2H), 7.95 (dd, 1H), 8.35 (s, 1H),8.68-8.72 (m, 3H), 8.78 (s, 1H), 9.51 (s, 1H).

Example 15-271-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,4-difluorophenyl)urea

TLC:Rf 0.40 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.55 (s, 2H), 7.00-7.09 (m, 1H), 7.27 (d, 2H),7.28-7.39 (m, 2H), 7.52 (d, 2H), 7.93 (d, 1H), 7.96-8.02 (m, 1H), 8.70(s, 1H), 8.71 (s, 2H), 9.15 (s, 1H).

Example 15-281-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-fluorophenyl)urea

TLC:Rf 0.50 (Ethyl Acetate:Hexane=3:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.03-7.06 (m, 1H), 7.12 (t, 1H),7.20-7.24 (m, 1H), 7.28 (d, 2H), 7.42 (d, 1H), 7.50 (dd, 2H), 7.95 (d,1H), 8.04 (t, 1H), 8.73 (s, 2H), 9.15 (br, 2H).

Example 15-291-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,4,6-trifluorophenyl)urea

TLC:Rf 0.60 (Hexane:Ethyl Acetate=1:9);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.24-7.30 (m, 4H), 7.42 (d, 1H), 7.49(d, 2H), 7.94 (d, 1H), 8.34 (s, 1H), 8.70 (s, 2H), 9.22 (s, 1H).

Example 15-301-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.50 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.56 (d, 2H), 7.27 (d, 2H), 7.36 (dd, 1H), 7.52 (d,2H), 7.53-7.55 (m, 2H), 7.70 (d, 1H), 7.89-7.94 (m, 2H), 8.24 (s, 1H),8.28 (d, 1H), 8.66 (s, 2H), 8.67-8.69 (m, 2H), 9.29 (s, 1H).

Example 15-311-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-chloro-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.40 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.27 (d, 2H), 7.42 (d, 1H), 7.46-7.55(m, 3H), 7.74 (d, 1H), 7.89 (d, 1H), 7.95 (d, 1H), 8.72 (s, 2H), 9.09(s, 1H), 9.55 (s, 1H).

Example 15-321-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3,4-difluorophenyl)urea

TLC:Rf 0.73 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.13-7.17 (m, 1H), 7.26 (d, 2H), 7.29(d, 1H), 7.38 (dd, 1H), 7.52 (d, 2H), 7.59-7.67 (m, 1H), 7.93 (d, 1H),8.70 (s, 2H), 8.93 (s, 1H), 9.16 (s, 1H).

Example 15-331-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.45 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.29 (d, 2H), 7.38 (dd, 1H), 7.52-7.56(m, 3H), 7.69-7.76 (m, 1H), 7.94 (d, 1H), 8.32-8.42 (m, 1H), 8.75 (s,2H), 9.12 (d, 1H), 9.33 (s, 1H).

Example 15-341-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,5-difluorophenyl)urea

TLC:Rf 0.80 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 6.81-6.87 (m, 1H), 7.25-7.58 (m, 2H),7.29 (d, 1H), 7.38 (dd, 1H), 7.53 (d, 2H), 7.92-8.00 (m, 2H), 8.73 (s,2H), 8.96 (s, 1H), 9.26 (s, 1H).

Example 15-351-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-chloro-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.40 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 7.28 (d, 2H), 7.39 (dd, 1H), 7.53 (d,3H), 7.75 (d, 1H), 7.94 (dd, 2H), 8.73 (s, 2H), 9.11 (s, 1H), 9.57 (s,1H).

Example 15-361-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.80 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.58 (s, 2H), 7.27 (d, 2H), 7.38 (dd, 1H), 7.54 (d,2H), 7.61-7.68 (m, 4H), 7.93 (d, 1H), 8.73 (s, 2H), 8.99 (s, 1H), 9.37(s, 1H).

Example 15-371-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(5-methyl-1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.54 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 2.18 (s, 3H), 5.85 (s, 2H), 6.40 (s, 1H), 7.26 (d,2H), 7.41 (d, 1H), 7.50 (d, 2H), 7.65 (d, 1H), 7.74 (d, 1H), 7.82 (d,1H), 7.95 (d, 1H), 8.31 (s, 1H), 8.47 (d, 1H), 8.67 (s, 2H), 9.75 (s,1H).

Example 15-381-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3,5-difluorophenyl)urea

TLC:Rf 0.68 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 6.81-6.87 (m, 1H), 7.19 (dd, 2H), 7.27(d, 2H), 7.42 (d, 1H), 7.50 (d, 1H), 7.52 (d, 2H), 7.96 (d, 1H), 8.71(s, 2H), 9.03 (s, 1H), 9.36 (s, 1H).

Example 15-391-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,4,6-trifluorophenyl)urea

TLC:Rf 0.59 (Hexane:Ethyl Acetate=1:9);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.25-7.30 (m, 4H), 7.37 (dd, 1H), 7.52(d, 2H), 7.93 (d, 1H), 8.35 (s, 1H), 8.70 (s, 2H), 9.24 (s, 1H).

Example 15-401-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.64 (Hexane:Ethyl Acetate=1:3);

¹H-NMR (DMSO-d₆): δ 5.84 (s, 2H), 7.08 (d, 1H), 7.16-7.20 (m, 2H), 7.20(d, 1H), 7.39-7.41 (m, 1H), 7.47-7.51 (m, 2H), 7.68 (dd, 1H), 7.87 (d,1H), 7.95 (d, 1H), 8.03 (dd, 1H), 8.24 (d, 1H), 8.45 (d, 1H), 8.68 (s,1H), 9.70 (s, 1H).

Example 15-411-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3,5-difluorophenyl)urea

TLC:Rf 0.68 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 6.81 (t, 1H), 7.20 (dd, 2H), 7.28 (d,2H), 7.38 (dd, 1H), 7.53 (d, 2H), 7.94 (d, 1H), 8.72 (s, 2H), 9.02 (s,1H), 9.35 (s, 1H).

Example 15-421-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,3,4-trifluorophenyl)urea

TLC:Rf 0.50 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.28 (d, 3H), 7.38 (dd, 1H), 7.53 (d,2H), 7.76-7.80 (m, 1H), 7.94 (s, 1H), 8.72 (s, 2H), 8.91 (s, 1H), 9.20(s, 1H).

Example 15-431-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,3-difluorophenyl)urea

TLC:Rf 0.49 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.05-7.16 (m, 2H), 7.29 (d, 2H), 7.38(dd, 1H), 7.53 (d, 2H), 7.63-7.66 (m, 1H), 7.87 (t, 1H), 7.94 (d, 1H),8.73 (s, 1H), 8.96 (s, 1H), 9.26 (s, 1H).

Example 15-441-(6-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyridin-3-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.52 (Hexane:Ethyl Acetate=1:3);

¹H-NMR (DMSO-d₆): δ 5.55 (s, 2H), 7.08 (d, 1H), 7.18 (d, 2H), 7.34 (dd,1H), 7.50 (d, 2H), 7.68 (d, 1H), 7.87 (s, 1H), 7.93 (d, 1H), 8.04 (dd,1H), 8.24 (d, 1H), 8.45 (d, 1H), 8.68 (s, 1H), 9.70 (s, 1H).

Example 15-451-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,6-difluorophenyl)urea

TLC:Rf 0.75 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 5.55 (s, 2H), 7.12-7.28 (m, 2H), 7.27 (d, 2H), 7.36(dd, 2H), 7.53 (d, 2H), 7.93 (d, 1H), 8.42 (s, 1H), 8.71 (s, 2H), 9.18(s, 1H).

Example 15-461-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2,3,5,6-tetrafluorophenyl)urea

TLC:Rf 0.50 (Ethyl Acetate:Hexane=2:1);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.28 (d, 2H), 7.38 (dd, 1H), 7.53 (d,2H), 7.74-7.88 (m, 1H), 7.94 (d, 1H), 8.72 (s, 2H), 8.89 (s, 1H), 9.33(s, 1H).

Example 15-471-(2-(4-(2-aminopyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(tert-butyl)-1-(o-tolyl)-1H-pyrazol-5-yl)urea

TLC:Rf 0.35 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 1.26 (s, 9H), 1.99 (s, 3H), 5.57 (s, 2H), 6.34 (s,1H), 6.66 (dd, 1H), 7.20-7.50 (m, 9H), 7.94 (dd, 1H), 8.39 (s, 1H), 8.64(s, 2H), 9.07 (s, 1H).

Example 15-481-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(tert-butyl)-1-(o-tolyl)-1H-pyrazol-5-yl)urea

TLC:Rf 0.71 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.26 (s, 9H), 1.99 (s, 3H), 5.84 (s, 2H), 6.34 (s,1H), 7.25 (d, 2H), 7.31-7.43 (m, 5H), 7.50 (d, 2H), 7.95 (d, 1H), 8.39(s, 1H), 8.64 (s, 2H), 9.07 (s, 1H).

Example 15-491-(2-(4-(2-aminopyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(tert-butyl)-1-(2,3-dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl)urea

TLC:Rf 0.68 (Ethyl Acetate:Methanol=10:1);

¹H-NMR (DMSO-d₆): δ 1.25 (s, 9H), 2.06 (quint., 2H), 2.85-2.94 (m, 4H),5.56 (s, 2H), 6.33 (s, 1H), 6.62-6.69 (m, 1H), 7.19-7.27 (m, 3H),7.30-7.37 (m, 3H), 7.47 (d, 2H), 7.92-7.96 (m, 1H), 8.56 (s, 1H), 8.66(s, 2H), 9.18 (s, 1H).

Example 15-501-(2-(4-(2-amino-5-methylpyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(tert-butyl)-1-(o-tolyl)-1H-pyrazol-5-yl)urea

TLC:Rf 0.67 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.26 (s, 9H), 1.99 (s, 3H), 2.15 (s, 3H), 5.33 (s,2H), 6.34 (s, 1H), 7.20-7.24 (m, 3H), 7.31-7.48 (m, 6H), 7.78 (s, 1H),8.39 (s, 1H), 8.64 (s, 2H), 9.06 (s, 1H).

Example 15-511-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 601 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.49 (s, 2H), 6.67-6.69 (m, 1H), 7.26-7.30 (m, 2H),7.50-7.56 (m, 4H), 7.76 (d, 1H), 7.95 (d, 1H), 8.26 (d, 1H), 8.41 (d,1H), 8.58 (d, 1H), 8.70 (s, 2H), 9.71 (s, 1H), 9.97 (s, 1H).

Example 15-521-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.07 minutes);

MASS (ESI, Pos.): 669 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.48 (s, 2H), 7.12 (d, 1H), 7.28 (d, 2H), 7.50-7.60(m, 4H), 7.71 (d, 1H), 8.27 (s, 1H), 8.48 (s, 2H), 8.59 (s, 1H), 8.67(s, 2H), 9.48 (s, 1H).

Example 15-531-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.00 minute);

MASS (ESI, Pos.): 568 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.25-7.30 (m, 2H), 7.43 (d, 1H),7.49-7.53 (m, 2H), 7.59 (dd, 1H), 7.95 (d, 1H), 8.07 (d, 1H), 8.33 (s,2H), 8.65 (d, 1H), 8.72 (s, 2H), 9.67 (s, 1H), 10.03 (s, 1H).

Example 15-541-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.97 minutes);

MASS (ESI, Pos.): 534 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.25-7.31 (m, 3H), 7.43 (d, 1H),7.49-7.53 (m, 2H), 7.80 (d, 1H), 7.95 (d, 1H), 8.26 (s, 2H), 8.32 (d,1H), 8.70 (s, 2H), 9.37 (s, 1H), 9.93 (s, 1H).

Example 15-551-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.61 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.26 (d, 2H), 7.40-7.60 (m, 10H), 7.95(d, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 8.66 (s, 2H), 9.39 (s, 1H).

Example 15-561-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(2-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.58 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.25 (s, 3H), 5.85 (s, 2H), 7.23-7.31 (m, 2H),7.35-7.56 (m, 6H), 7.60-7.68 (m, 1H), 7.88 (s, 1H), 7.94-7.98 (m, 1H),8.52-8.56 (m, 1H), 8.58-8.62 (m, 1H), 8.65 (s, 2H), 9.29 (s, 1H).

Example 15-571-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-phenyl-2-(trifluoromethyl)-4-pyridinyl]urea

TLC:Rf 0.38 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.25-7.31 (m, 2H), 7.42 (d, 1H),7.50-7.66 (m, 7H), 7.95 (d, 1H), 8.43-8.46 (m, 2H), 8.69 (s, 2H), 8.75(s, 1H), 9.74 (s, 1H).

Example 15-581-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.60 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 7.23-7.29 (m, 2H), 7.34-7.58 (m, 10H),7.92-7.96 (m, 1H), 8.09 (s, 1H), 8.41 (s, 1H), 8.66 (s, 2H), 9.39 (s,1H).

Example 15-591-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(4-fluoro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.56 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.24-7.32 (m, 2H), 7.42 (d, 1H),7.48-7.58 (m, 3H), 7.67-7.73 (m, 1H), 7.95 (d, 1H), 8.03-8.07 (m, 1H),8.56-8.60 (m, 2H), 8.70 (s, 2H), 9.27 (s, 1H), 9.85 (s, 1H).

Example 15-601-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(4-fluoro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.50 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 7.26-7.32 (m, 2H), 7.38 (dd, 1H),7.51-7.59 (m, 3H), 7.66-7.73 (m, 1H), 7.94 (d, 1H), 8.03-8.07 (m, 1H),8.55-8.60 (m, 2H), 8.70 (s, 2H), 9.27 (s, 1H), 9.85 (s, 1H).

Example 15-611-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-phenyl-5-(trifluoromethyl)-3-pyridinyl]urea

TLC:Rf 0.43 (Hexane:Ethyl Acetate=1:3);

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.26 (d, 2H), 7.42 (d, 1H), 7.49-7.70(m, 7H), 7.95 (d, 1H), 8.43 (s, 1H), 8.68 (s, 2H), 8.73 (s, 1H), 8.76(s, 1H), 9.47 (s, 1H).

Example 15-621-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3′,4′-dimethyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.72 (Hexane:Ethyl Acetate=1:3);

¹H-NMR (DMSO-d₆): δ 2.29 (s, 6H), 5.85 (s, 2H), 7.12-7.55 (m, 10H), 7.95(d, 1H), 8.01 (s, 1H), 8.44 (s, 1H), 8.66 (s, 2H), 9.44 (s, 1H).

Example 15-631-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.43 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.24-7.30 (m, 2H), 7.42 (d, 1H),7.47-7.57 (m, 3H), 7.70 (d, 1H), 7.95 (d, 1H), 8.07 (s, 1H), 8.57 (d,1H), 8.63 (s, 1H), 8.70 (s, 2H), 9.11 (s, 1H), 9.81 (s, 1H).

Example 15-641-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.63 (Methylene Chloride:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 2.39 (s, 3H), 5.86 (brs, 2H), 7.26 (d, 2H),7.29-7.49 (m, 7H), 7.50 (d, 2H), 7.95 (d, 1H), 8.05 (s, 1H), 8.43 (s,1H), 8.67 (s, 2H), 9.42 (s, 1H).

Example 15-651-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.55 (Methylene Chloride:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 2.39 (s, 3H), 5.56 (brs, 2H), 7.26 (d, 2H),7.29-7.48 (m, 7H), 7.52 (d, 2H), 7.94 (d, 1H), 8.05 (s, 1H), 8.43 (s,1H), 8.67 (s, 2H), 9.42 (s, 1H).

Example 15-661-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.58 (Methylene Chloride:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 2.39 (s, 3H), 5.86 (brs, 2H), 7.19-7.55 (m, 11H),7.95 (d, 1H), 8.04 (s, 1H), 8.43 (s, 1H), 8.66 (s, 2H), 9.43 (s, 1H).

Example 15-671-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.53 (Methylene Chloride:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 2.38 (s, 3H), 5.57 (brs, 2H), 7.19-7.48 (m, 9H),7.52 (d, 2H), 7.94 (d, 1H), 8.04 (s, 1H), 8.44 (s, 1H), 8.66 (s, 2H),9.43 (s, 1H).

Example 15-681-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{2-[4-(difluoromethyl)-1H-pyrazol-1-yl]-5-(trifluoromethyl)phenyl}urea

TLC:Rf 0.20 (Hexane:Ethyl Acetate:Methanol=6:4:0.4);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.16 (t, 1H), 7.26 (d, 2H), 7.41 (d,1H), 7.48-7.57 (m, 3H), 7.74 (d, 1H), 7.94 (d, 1H), 8.17 (s, 1H), 8.55(d, 1H), 8.69 (s, 2H), 8.70 (s, 1H), 9.19 (s, 1H), 9.85 (s, 1H).

Example 15-691-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{2-[4-(difluoromethyl)-1H-pyrazol-1-yl]-5-(trifluoromethyl)phenyl}urea

TLC:Rf 0.16 (Hexane:Ethyl Acetate:Methanol=6:4:0.4);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.16 (t, 1H), 7.26 (d, 2H), 7.36 (dd,1H), 7.49-7.57 (m, 3H), 7.74 (d, 1H), 7.92 (d, 1H), 8.18 (s, 1H), 8.55(d, 1H), 8.69 (s, 2H), 8.70 (s, 1H), 9.19 (s, 1H), 9.85 (s, 1H).

Example 15-701-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{5-chloro-2-[4-(difluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

TLC:Rf 0.17 (Hexane:Ethyl Acetate:Methanol=6:4:0.4);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.14 (t, 1H), 7.22-7.29 (m, 3H), 7.41(d, 1H), 7.47-7.53 (m, 3H), 7.94 (d, 1H), 8.12 (s, 1H), 8.24 (d, 1H),8.58 (s, 1H), 8.68 (s, 2H), 8.91 (s, 1H) 9.78 (s, 1H).

Example 15-711-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{5-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

TLC:Rf 0.21 (Hexane:Ethyl Acetate:Methanol=6:4:0.4);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.07 (s, 1H), 7.22-7.31 (m, 3H),7.39-7.53 (m, 4H), 7.94 (d, 1H), 8.18 (s, 1H), 8.37 (d, 2H), 8.65 (s,2H), 9.43 (s, 1H).

Example 15-721-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{5-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

TLC:Rf 0.29 (Hexane:Ethyl Acetate=2:3);

¹H-NMR (DMSO-d₆): δ 1.25 (t, 3H), 2.69 (q, 2H), 5.86 (s, 2H), 7.20-7.55(m, 11H), 7.95 (d, 1H), 8.09 (s, 1H), 8.40 (s, 1H), 8.66 (s, 2H), 9.40(s, 1H).

Example 15-731-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3′-ethyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.32 (Hexane:Ethyl Acetate=2:3);

¹H-NMR (DMSO-d₆): δ 1.22 (t, 3H), 2.68 (q, 2H), 5.85 (s, 2H), 7.24-7.55(m, 11H), 7.94 (d, 1H), 8.06 (s, 1H), 7.38-7.42 (m, 1H), 8.65 (s, 2H),9.41 (s, 1H).

Example 15-741-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3′-ethyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.33 (Hexane:Ethyl Acetate=2:3);

¹H-NMR (DMSO-d₆): δ 1.22 (t, 3H), 2.68 (q, 2H), 5.57 (s, 2H), 7.24-7.56(m, 11H), 7.94 (d, 1H), 8.07 (s, 1H), 8.39 (s, 1H), 8.66 (s, 2H), 9.41(s, 1H).

Example 15-751-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-methoxy-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.94 minutes);

MASS (ESI, Pos.): 531 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.97 (s, 3H), 5.86 (s, 2H), 7.25-7.33 (m, 4H), 7.43(d, 1H), 7.49-7.56 (m, 2H), 7.96 (d, 1H), 8.32 (d, 1H), 8.70 (s, 1H),8.73 (s, 2H), 9.66 (s, 1H).

Example 15-761-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.90 minutes);

MASS (ESI, Pos.): 579 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.42 (s, 3H), 5.87 (s, 2H), 7.26-7.33 (m, 2H), 7.43(d, 1H), 7.47-7.57 (m, 2H), 7.96 (dd, 1H), 8.04-8.12 (m, 2H), 8.50 (d,1H), 8.76 (s, 2H), 9.04 (s, 1H), 10.36 (s, 1H).

Example 15-771-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2,4-bis(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.98 minutes);

MASS (ESI, Pos.): 569 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.26-7.34 (m, 2H), 7.42-7.44 (m, 1H),7.49-7.56 (m, 2H), 7.95-7.99 (m, 2H), 8.04 (d, 1H), 8.33 (d, 1H), 8.56(s, 1H), 8.75 (s, 2H), 9.80 (s, 1H).

Example 15-781-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(5-chloro-2-methylphenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.88 minutes);

MASS (ESI, Pos.): 481 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.22 (s, 3H), 5.86 (s, 2H), 7.01 (dd, 1H), 7.20 (d,1H), 7.25-7.32 (m, 2H), 7.43 (d, 1H), 7.48-7.55 (m, 2H), 7.95-7.99 (m,2H), 8.26 (s, 1H), 8.74 (s, 2H), 9.30 (s, 1H).

Example 15-791-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(5-chloro-2-methylphenyl)urea

TLC:Rf 0.32 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.23-7.30 (m, 2H), 7.42 (d, 1H),7.46-7.56 (m, 3H), 7.70 (d, 1H), 7.95 (d, 1H), 8.06 (s, 1H), 8.56 (d,1H), 8.62 (s, 1H), 8.69 (s, 2H), 9.11 (s, 1H), 9.81 (s, 1H).

Example 15-801-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{5-(difluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

TLC:Rf 0.47 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.08 (d, 1H), 7.13 (t, 1H), 7.25 (d,2H), 7.39-7.44 (m, 2H), 7.50 (d, 2H), 7.60 (d, 1H), 7.94 (d, 1H), 8.28(s, 1H), 8.40-8.43 (d, 1H), 8.46 (s, 1H), 8.66 (s, 2H), 9.42 (s, 1H).

Example 15-811-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{4-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

TLC:Rf 0.51 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.84 (s, 2H), 7.05 (d, 1H), 7.24 (d, 2H), 7.40 (d,1H), 7.52 (d, 2H), 7.53-7.61 (m, 2H), 7.94 (d, 1H), 8.01 (d, 1H), 8.35(s, 1H), 8.37-8.42 (m, 1H), 8.63 (s, 2H), 9.35 (s, 1H).

Example 15-821-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-{2-[3-(difluoromethyl)-1H-pyrazol-1-yl]-5-(trifluoromethyl)phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.04 minutes);

MASS (ESI, Pos.): 651 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.48 (s, 2H), 6.93 (d, 1H), 7.14 (t, 1H), 7.26-7.33(m, 2H), 7.49-7.60 (m, 4H), 7.73 (d, 1H), 8.27 (d, 1H), 8.45 (d, 1H),8.54 (d, 1H), 8.69 (s, 2H), 8.95 (s, 1H), 9.66 (s, 1H).

Example 15-831-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.02 minutes);

MASS (ESI, Pos.): 670 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.48 (s, 2H), 7.25-7.32 (m, 2H), 7.48-7.58 (m, 3H),7.72 (dd, 1H), 7.82 (d, 1H), 8.27 (d, 1H), 8.49 (d, 1H), 8.66-8.69 (m,3H), 9.24 (s, 1H), 9.33 (s, 1H).

Example 15-841-[2-(3-acetyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]-3-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 643 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.59 (s, 3H), 6.48 (s, 2H), 7.04-7.07 (m, 1H),7.24-7.32 (m, 2H), 7.48-7.62 (m, 4H), 7.75 (d, 1H), 8.25-8.29 (m, 1H),8.40 (d, 1H), 8.63 (d, 1H), 8.68 (s, 2H), 8.75 (s, 1H), 9.64 (s, 1H).

Example 15-851-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(2-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.84 minutes);

MASS (ESI, Pos.): 626 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.25 (s, 3H), 6.48 (s, 2H), 7.23-7.57 (m, 8H), 7.63(dd, 1H), 7.88 (s, 1H), 8.27 (d, 1H), 8.53 (s, 1H), 8.59 (dd, 1H), 8.65(s, 2H), 9.29 (s, 1H).

Example 15-861-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(4-fluoro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.02 minutes);

MASS (ESI, Pos.): 619 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.49 (s, 2H), 7.26-7.33 (m, 2H), 7.48-7.58 (m, 4H),7.68 (d, 1H), 8.03-8.07 (m, 1H), 8.26-8.30 (m, 1H), 8.56-8.63 (m, 2H),8.70 (s, 2H), 9.27 (s, 1H), 9.85 (s, 1H).

Example 15-871-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.06 minutes);

MASS (ESI, Pos.): 635 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.49 (s, 2H), 7.26-7.32 (m, 2H), 7.50-7.59 (m, 4H),7.70 (d, 1H), 8.07-8.09 (m, 1H), 8.26-8.30 (m, 1H), 8.57 (d, 1H),8.63-8.64 (m, 1H), 8.69 (s, 2H), 9.11 (s, 1H), 9.81 (s, 1H).

Example 15-881-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-chloro-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.04 minutes);

MASS (ESI, Pos.): 569 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.49 (s, 2H), 7.27-7.34 (m, 2H), 7.50-7.60 (m, 3H),7.70 (dd, 1H), 7.89-7.93 (m, 1H), 8.26-8.31 (m, 1H), 8.43 (d, 1H), 8.75(s, 2H), 8.81 (s, 1H), 9.78 (s, 1H).

Example 15-891-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-chloro-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.02 minutes);

MASS (ESI, Pos.): 569 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.49 (s, 2H), 7.26-7.34 (m, 2H), 7.40 (dd, 1H),7.50-7.59 (m, 3H), 7.73 (d, 1H), 8.26-8.30 (m, 1H), 8.56 (d, 1H), 8.75(s, 2H), 8.79 (s, 1H), 9.72 (s, 1H).

Example 15-901-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.98 minutes);

MASS (ESI, Pos.): 553 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.49 (s, 2H), 7.26-7.33 (m, 2H), 7.38-7.59 (m, 5H),8.26-8.30 (m, 1H), 8.52 (dd, 1H), 8.75 (s, 2H), 9.11 (s, 1H), 9.31 (s,1H).

Example 15-911-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-(2,5-dichlorophenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 535 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.49 (s, 2H), 7.12 (dd, 1H), 7.27-7.34 (m, 2H),7.50-7.59 (m, 4H), 8.26-8.30 (m, 2H), 8.65 (s, 1H), 8.74 (s, 2H), 9.68(s, 1H).

Example 15-921-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-(2,4-dichlorophenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.00 minute);

MASS (ESI, Pos.): 535 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.49 (s, 2H), 7.27-7.33 (m, 2H), 7.39 (dd, 1H),7.50-7.59 (m, 3H), 7.64 (d, 1H), 8.14 (d, 1H), 8.27-8.30 (m, 1H), 8.59(s, 1H), 8.73 (s, 2H), 9.60 (s, 1H).

Example 15-931-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-methyl-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.98 minutes);

MASS (ESI, Pos.): 549 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32 (s, 3H), 6.49 (s, 2H), 7.27-7.34 (m, 3H), 7.42(d, 1H), 7.50-7.59 (m, 3H), 8.26-8.30 (m, 2H), 8.39 (s, 1H), 8.75 (s,2H), 9.34 (s, 1H).

Example 15-941-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-isopropyl-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.67 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 1.22 (d, 6H), 3.21 (m, 1H), 5.86 (s, 2H), 7.25-7.31(m, 2H), 7.39-7.56 (m, 5H), 7.95 (d, 1H), 8.12-8.15 (m, 1H), 8.43 (s,1H), 8.74 (s, 2H), 9.28 (s, 1H).

Example 15-951-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-ethyl-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.35 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 1.20 (t, 3H), 2.69 (q, 2H), 5.86 (s, 2H), 7.25-7.31(m, 2H), 7.33-7.46 (m, 3H), 7.48-7.56 (m, 2H), 7.95 (d, 1H), 8.24-8.27(m, 1H), 8.38 (m, 1H), 8.75 (s, 2H), 9.34 (s, 1H).

Example 15-961-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.44 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 3.38 (s, 3H), 5.57 (s, 2H), 7.25-7.31 (m, 2H), 7.37(dd, 1H), 7.48-7.56 (m, 2H), 7.61-7.67 (m, 1H), 7.93 (d, 1H), 8.04-8.09(m, 1H), 8.61-8.65 (m, 1H), 8.75 (s, 2H), 8.97 (s, 1H), 10.30 (s, 1H).

Example 15-971-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)-4-(trifluoromethyl)phenyl]urea

TLC:Rf 0.31 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 3.42 (s, 3H), 6.49 (s, 2H), 7.27-7.33 (m, 2H),7.49-7.58 (m, 3H), 8.03-8.11 (m, 2H), 8.25-8.30 (m, 1H), 8.50 (d, 1H),8.76 (s, 2H), 9.04 (s, 1H), 10.36 (s, 1H).

Example 15-981-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.32 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 3.38 (s, 3H), 6.49 (s, 2H), 7.24-7.32 (m, 2H),7.48-7.58 (m, 3H), 7.64 (d, 1H), 8.06 (d, 1H), 8.24-8.29 (m, 1H),8.61-8.64 (m, 1H), 8.75 (s, 2H), 8.97 (s, 1H), 10.30 (s, 1H).

Example 15-991-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.28 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.27 (d, 2H), 7.36 (dd, 1H), 7.51-7.57(m, 3H), 7.68-7.74 (m, 1H), 7.93 (d, 1H), 8.06 (s, 1H), 8.56 (s, 1H),8.62 (s, 1H), 8.69 (s, 2H), 9.10 (s, 1H), 9.80 (s, 1H).

Example 15-1001-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-methyl-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.94 minutes);

MASS (ESI, Pos.): 515 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.36 (s, 3H), 5.86 (s, 2H), 7.15 (s, 1H), 7.26 (d,2H), 7.40-7.45 (m, 2H), 7.50 (d, 2H), 7.76 (s, 1H), 7.95 (d, 1H), 8.73(s, 2H), 8.98 (s, 1H), 9.23 (s, 1H).

Example 15-1011-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-methyl-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.93 minutes);

MASS (ESI, Pos.): 515 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32 (s, 3H), 5.86 (s, 2H), 7.27 (d, 2H), 7.45 (d,1H), 7.47-7.54 (m, 3H), 7.56 (s, 1H), 7.95 (d, 1H), 8.14 (d, 1H), 8.40(s, 1H), 8.75 (s, 2H), 9.39 (s, 1H).

Example 15-1021-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2,5-bis(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.97 minutes);

MASS (ESI, Pos.): 569 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.27 (d, 2H), 7.42 (d, 1H), 7.50 (d,2H), 7.63 (d, 1H), 7.90-7.97 (m, 2H), 8.41 (s, 1H), 8.57 (s, 1H), 8.74(s, 2H), 9.73 (s, 1H).

Example 15-1031-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-methoxy-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.93 minutes);

MASS (ESI, Pos.): 531 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.96 (s, 3H), 5.86 (s, 2H), 7.17-7.37 (m, 4H), 7.42(d, 1H), 7.50 (d, 2H), 7.95 (d, 1H), 8.48 (d, 1H), 8.66 (s, 1H), 8.72(s, 2H), 9.60 (s, 1H).

Example 15-1041-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.91 minutes);

MASS (ESI, Pos.): 579 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.38 (s, 3H), 5.87 (s, 2H), 7.25-7.31 (m, 2H), 7.43(d, 1H), 7.48-7.54 (m, 2H), 7.62-7.67 (m, 1H), 7.96 (d, 1H), 8.07 (d,1H), 8.61-8.65 (m, 1H), 8.75 (s, 2H), 8.97 (s, 1H), 10.31 (s, 1H).

Example 15-1052-{[(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)carbamoyl]amino}-N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide

TLC:Rf 0.64 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 2.76 (s, 6H), 6.49 (s, 2H), 7.27-7.35 (m, 2H),7.50-7.65 (m, 4H), 7.94 (d, 1H), 8.26-8.30 (m, 1H), 8.61 (s, 1H), 8.74(s, 2H), 8.99 (s, 1H), 10.31 (s, 1H).

Example 15-1061-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3′-(hydroxymethyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.95 minutes);

MASS (ESI, Pos.): 607 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.59 (d, 2H), 5.28 (t, 1H), 5.86 (s, 2H), 7.22-7.33(m, 3H), 7.36 (s, 1H), 7.37-7.53 (m, 7H), 7.93-7.98 (m, 1H), 8.06 (s,1H), 8.42 (s, 1H), 8.66 (s, 2H), 9.42 (s, 1H).

Example 15-1071-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3′-(hydroxymethyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 0.88 minutes);

MASS (ESI, Pos.): 591 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.58 (d, 2H), 5.28 (t, 1H), 5.57 (s, 2H), 7.22-7.32(m, 3H), 7.35-7.56 (m, 8H), 7.94 (d, 1H), 8.06 (s, 1H), 8.42 (s, 1H),8.66 (s, 2H), 9.42 (s, 1H).

Example 15-1081-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3′-(1-hydroxyethyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.98 minutes);

MASS (ESI, Pos.): 621 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.36 (d, 3H), 4.74-4.93 (m, 1H), 5.21 (d, 1H), 5.86(s, 2H), 7.22-7.36 (m, 3H), 7.38-7.56 (m, 8H), 7.95 (d, 1H), 8.09 (s,1H), 8.37 (s, 1H), 8.66 (s, 2H), 9.40 (s, 1H).

Example 15-1091-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3′-(1-hydroxyethyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.91 minutes);

MASS (ESI, Pos.): 605 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.36 (d, 3H), 4.74-4.93 (m, 1H), 5.21 (d, 1H), 5.57(s, 2H), 7.22-7.57 (m, 11H), 7.94 (d, 1H), 8.09 (s, 1H), 8.37 (s, 1H),8.66 (s, 2H), 9.40 (s, 1H).

Example 15-1101-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(ethylsulfonyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.59 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 1.15 (t, 3H), 3.45 (q, 2H), 6.48 (s, 2H), 7.27 (d,2H), 7.51 (d, 2H), 7.55 (d, 1H), 7.62 (d, 1H), 8.02 (d, 1H), 8.24-8.28(m, 1H), 8.64 (s, 1H), 8.74 (s, 2H), 9.00 (s, 1H), 10.32 (s, 1H).

Example 15-1111-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-chloro-2-(methylsulfonyl)phenyl]urea

TLC:Rf 0.38 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 3.33 (s, 3H), 5.86 (s, 2H), 7.25-7.31 (m, 2H), 7.36(dd, 1H), 7.43 (d, 1H), 7.48-7.55 (m, 2H), 7.85 (d, 1H), 7.96 (dd, 1H),8.33 (d, 1H), 8.75 (s, 2H), 8.88 (s, 1H), 10.26 (s, 1H).

Example 15-1121-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[5-fluoro-2-(methylsulfonyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.92 minutes);

MASS (ESI, Pos.): 563 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.31 (s, 3H), 6.49 (s, 2H), 7.09-7.19 (m, 1H), 7.29(d, 2H), 7.50-7.60 (m, 3H), 7.92 (dd, 1H), 8.11 (dd, 1H), 8.25-8.32 (m,1H), 8.75 (s, 2H), 8.95 (s, 1H), 10.29 (s, 1H).

Example 15-1132-{[(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)carbamoyl]amino}-4-fluoro-N,N-dimethylbenzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 0.98 minutes);

MASS (ESI, Pos.): 592 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.70 (s, 6H), 6.49 (s, 2H), 7.09-7.18 (m, 1H), 7.28(d, 2H), 7.48-7.59 (m, 3H), 7.80 (dd, 1H), 8.11 (dd, 1H), 8.25-8.30 (m,1H), 8.74 (s, 2H), 8.98 (s, 1H), 10.29 (s, 1H).

Example 15-1141-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylthio)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.25 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.53 (s, 3H), 5.56 (s, 2H), 7.26 (d, 2H), 7.35-7.43(m, 2H), 7.49-7.56 (m, 3H), 7.92 (d, 1H), 8.18 (d, 1H), 8.44 (s, 1H),8.73 (s, 2H), 9.64 (s, 1H).

Example 15-1151-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.34 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.88 (s, 3H), 6.47 (s, 2H), 7.27 (d, 2H), 7.48-7.57(m, 3H), 7.65 (d, 1H), 7.90 (d, 1H), 8.26 (s, 2H), 8.73 (s, 2H), 9.25(s, 1H), 9.68 (s, 1H).

Example 15-1161-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.32 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.88 (s, 3H), 5.56 (s, 2H), 7.27 (d, 2H), 7.36 (dd,1H), 7.52 (d, 2H), 7.65 (d, 1H), 7.88-7.94 (m, 2H), 8.26 (s, 1H), 8.73(s, 2H), 9.24 (s, 1H), 9.68 (s, 1H).

Example 15-1171-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[5-chloro-2-(methylsulfinyl)phenyl]urea

TLC:Rf 0.43 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.86 (s, 3H), 6.48 (s, 2H), 7.27 (d, 2H), 7.35 (dd,1H), 7.51 (d, 2H), 7.55 (d, 1H), 7.67 (d, 1H), 8.00 (d, 1H), 8.25-8.29(m, 1H), 8.73 (s, 2H), 9.24 (s, 1H), 9.69 (s, 1H).

Example 15-1181-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3′-(2-hydroxy-2-propanyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.00 minute);

MASS (ESI, Pos.): 635 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.45 (s, 6H), 5.07 (s, 1H), 5.85 (s, 2H), 7.21-7.33(m, 3H), 7.40-7.60 (m, 8H), 7.95 (d, 1H), 8.10 (s, 1H), 8.34 (s, 1H),8.65 (s, 2H), 9.38 (s, 1H).

Example 15-1191-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[3′-(2-hydroxy-2-propanyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.06 minutes);

MASS (ESI, Pos.): 669 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.45 (s, 6H), 5.07 (s, 1H), 6.48 (s, 2H), 7.22-7.34(m, 3H), 7.41-7.60 (m, 8H), 8.10 (s, 1H), 8.25-8.29 (m, 1H), 8.34 (s,1H), 8.65 (s, 2H), 9.39 (s, 1H).

Example 15-1201-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-chloro-2-(1H-pyrazol-1-yl)phenyl]urea

TLC:Rf 0.43 (Hexane:Ethyl Acetate=3:7);

¹H-NMR (DMSO-d₆): δ 5.87 (s, 2H), 6.63-6.64 (m, 1H), 7.23 (d, 1H),7.24-7.28 (m, 2H), 7.40-7.55 (m, 4H), 7.91 (d, 1H), 7.96 (d, 1H), 8.27(d, 1H), 8.30 (d, 1H), 8.70 (s, 2H), 9.40 (s, 1H), 9.91 (s, 1H).

Example 15-1211-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-chloro-2-(1H-pyrazol-1-yl)phenyl]urea

TLC:Rf 0.52 (Hexane:Ethyl Acetate=3:7);

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 6.61-6.65 (m, 1H), 7.26 (d, 2H),7.41-7.47 (m, 2H), 7.52 (d, 2H), 7.64 (d, 1H), 7.91 (d, 1H), 7.96 (d,1H), 8.14 (d, 1H), 8.36 (d, 1H), 8.69 (s, 2H), 9.37 (s, 1H), 9.85 (s,1H).

Example 15-1221-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 568 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.26 (d, 2H), 7.42 (d, 1H), 7.50 (d,2H), 7.89-7.92 (m, 2H), 7.95 (d, 1H), 8.09 (s, 1H), 8.45 (d, 1H),8.68-8.70 (m, 4H), 9.69 (brs, 1H).

Example 15-1231-{6-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-3-pyridinyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.99 minutes);

MASS (ESI, Pos.): 518 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.07 (d, 1H), 7.17 (d, 2H), 7.39-7.53(m, 5H), 7.94 (d, 1H), 8.05 (dd, 1H), 8.22 (d, 1H), 8.56 (dd, 1H), 8.96(d, 1H), 9.25 (s, 1H).

Example 15-1241-{6-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-3-pyridinyl}-3-[2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 566 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 6.65 (t, 1H), 7.05 (d, 1H), 7.16 (d,2H), 7.40 (d, 1H), 7.47 (d, 2H), 7.74 (d, 1H), 7.81 (d, 1H), 7.93-8.00(m, 3H), 8.22 (d, 1H), 8.42-8.44 (m, 2H), 9.42 (s, 1H), 9.84 (s, 1H).

Example 15-1251-{6-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-3-pyridinyl}-3-[2-(1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.93 minutes);

MASS (ESI, Pos.): 567 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.04 (d, 1H), 7.16 (d, 2H), 7.40 (d,1H), 7.47 (d, 2H), 7.59 (dd, 1H), 7.72 (d, 1H), 7.94 (d, 1H), 7.99 (dd,1H), 8.10 (d, 1H), 8.15 (d, 1H), 8.59-8.61 (m, 2H), 8.69 (s, 1H), 9.57(s, 1H).

Example 15-1261-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-chloro-2-(3-pyridinyl)phenyl]urea

Purity (LC-MS/ELSD): 98% (Retention Time: 0.79 minutes);

MASS (ESI, Pos.): 544 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.23-7.30 (m, 4H), 7.42 (d, 1H),7.49-7.55 (m, 3H), 7.80-7.85 (m, 1H), 7.95 (d, 1H), 8.08 (d, 1H), 8.14(s, 1H), 8.56-8.65 (m, 4H), 9.21 (s, 1H).

Example 15-1271-{2-[4-(2-amino-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.76 minutes);

MASS (ESI, Pos.): 533 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.58 (s, 2H), 6.64-6.68 (m, 2H), 7.26 (d, 2H), 7.35(dd, 1H), 7.47-7.54 (m, 3H), 7.75 (d, 1H), 7.93-7.95 (m, 2H), 8.42 (d,1H), 8.59 (d, 1H), 8.70 (s, 2H), 9.60-10.08 (br, 2H).

Example 15-1281-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.90 minutes);

MASS (ESI, Pos.): 612 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.48 (s, 2H), 7.24-7.29 (m, 2H), 7.50-7.58 (m, 6H),7.86-7.91 (m, 1H), 8.25-8.28 (m, 2H), 8.38 (d, 1H), 8.62-8.71 (m, 4H),9.25 (s, 1H).

Example 15-1291-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.93 minutes);

MASS (ESI, Pos.): 602 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.48 (s, 2H), 7.28 (d, 2H), 7.50-7.56 (m, 3H), 7.61(dd, 1H), 7.74 (d, 1H), 8.10 (s, 1H), 8.27 (d, 1H), 8.58 (d, 1H),8.69-8.73 (m, 4H), 9.67 (s, 1H).

Example 15-1301-{6-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-3-pyridinyl}-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.08 minutes);

MASS (ESI, Pos.): 634 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.04 (d, 1H), 7.14-7.18 (m, 3H), 7.40(d, 1H), 7.45-7.49 (m, 2H), 7.56 (dd, 1H), 7.69 (d, 1H), 7.94 (d, 1H),7.98 (dd, 1H), 8.16 (d, 1H), 8.45 (s, 1H), 8.47 (d, 1H), 8.51 (d, 1H),9.40 (s, 1H).

Example 15-1311-{6-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-3-pyridinyl}-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 618 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.55 (s, 2H), 7.04 (d, 1H), 7.14-7.18 (m, 3H), 7.41(dd, 1H), 7.46-7.51 (m, 2H), 7.55 (dd, 1H), 7.68 (d, 1H), 7.92 (d, 1H),7.97 (dd, 1H), 8.15 (d, 1H), 8.44 (s, 1H), 8.46-8.47 (m, 1H), 8.51 (d,1H), 9.39 (s, 1H).

Example 15-1321-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.93 minutes);

MASS (ESI, Pos.): 567 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.87 (s, 2H), 6.58-6.59 (m, 1H), 7.28 (d, 2H), 7.43(d, 1H), 7.49-7.54 (m, 2H), 7.80-7.84 (m, 3H), 8.00 (d, 1H), 8.25 (s,1H), 8.63 (d, 1H), 8.75 (s, 2H), 9.09 (s, 1H), 9.55 (s, 1H).

Example 15-1331-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.82 minutes);

MASS (ESI, Pos.): 578 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.87 (s, 2H), 7.28 (d, 2H), 7.43 (d, 1H), 7.50-7.55(m, 3H), 7.66 (s, 1H), 7.95-7.96 (m, 2H), 8.01 (s, 1H), 8.09-8.13 (m,1H), 8.62-8.64 (m, 1H), 8.75 (s, 2H), 8.90 (d, 1H), 9.13 (s, 1H), 9.44(s, 1H).

Example 15-1341-{6-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-3-pyridinyl}-3-[2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.96 minutes);

MASS (ESI, Pos.): 581 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.39 (s, 3H), 5.84 (s, 2H), 7.04 (d, 1H), 7.14-7.17(m, 2H), 7.39 (d, 1H), 7.45-7.48 (m, 2H), 7.56 (dd, 1H), 7.67 (d, 1H),7.93 (d, 1H), 7.99 (dd, 1H), 8.15 (d, 1H), 8.38 (d, 1H), 8.61-8.62 (m,2H), 9.59 (s, 1H).

Example 15-1351-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]urea

Purity (LC-MS/ELSD): 98% (Retention Time: 0.85 minutes);

MASS (ESI, Pos.): 534 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.24-7.29 (m, 2H), 7.32 (dd, 1H), 7.42(d, 1H), 7.48-7.53 (m, 3H), 7.95 (d, 1H), 8.06 (d, 1H), 8.27 (d, 1H),8.51 (s, 1H), 8.59 (d, 1H), 8.67 (s, 2H), 9.60 (s, 1H).

Example 15-1361-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(5-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.58 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.38 (s, 3H), 5.86 (s, 2H), 7.24-7.31 (m, 2H),7.40-7.54 (m, 5H), 7.70-7.74 (m, 1H), 7.95 (d, 1H), 8.20 (s, 1H),8.40-8.47 (m, 2H), 8.51-8.55 (m, 1H), 8.66 (s, 2H), 9.28 (s, 1H).

Example 15-1371-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(5-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.45 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.38 (s, 3H), 5.57 (s, 2H), 7.22-7.31 (m, 2H), 7.37(dd, 1H), 7.43-7.58 (m, 4H), 7.68-7.75 (m, 1H), 7.93 (d, 1H), 8.20 (s,1H), 8.40-8.46 (m, 2H), 8.51-8.55 (m, 1H), 8.66 (s, 2H), 9.29 (s, 1H).

Example 15-1381-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(2-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.18 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.25 (s, 3H), 5.56 (s, 2H), 7.22-7.30 (m, 2H),7.33-7.56 (m, 6H), 7.59-7.66 (m, 1H), 7.87 (s, 1H), 7.93 (d, 1H), 8.53(s, 1H), 8.56-8.61 (m, 1H), 8.65 (s, 2H), 9.28 (s, 1H).

Example 15-1391-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-phenyl-2-(trifluoromethyl)-4-pyridinyl]urea

TLC:Rf 0.44 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 7.25-7.32 (m, 2H), 7.37 (dd, 1H),7.50-7.65 (m, 7H), 7.94 (d, 1H), 8.42-8.47 (m, 2H), 8.69 (s, 2H), 8.75(s, 1H), 9.74 (s, 1H).

Example 15-1401-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(6-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.68 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 2.55 (s, 3H), 5.85 (s, 2H), 7.26 (d, 2H), 7.42-7.53(m, 6H), 7.76 (dd, 1H), 7.95 (d, 1H), 8.20 (s, 1H), 8.42 (s, 1H), 8.50(d, 1H), 8.67 (s, 2H), 9.28 (s, 1H).

Example 15-1411-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-phenyl-5-(trifluoromethyl)-3-pyridinyl]urea

TLC:Rf 0.43 (Hexane:Ethyl Acetate=1:3);

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 7.27 (d, 2H), 7.38 (dd, 1H), 7.51-7.69(m, 7H), 7.94 (d, 1H), 8.43 (s, 1H), 8.68 (s, 2H), 8.73 (s, 1H), 8.76(s, 1H), 9.47 (s, 1H).

Example 15-1421-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3′,4′-dimethyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.79 (Hexane:Ethyl Acetate=1:3);

¹H-NMR (DMSO-d₆): δ 2.29 (s, 6H), 5.56 (s, 2H), 7.13-7.56 (m, 10H), 7.93(d, 1H), 8.01 (s, 1H), 8.45 (s, 1H), 8.67 (s, 1H), 9.45 (s, 1H).

Example 15-1431-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(6-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.69 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 2.55 (s, 3H), 5.56 (s, 2H), 7.26 (d, 2H), 7.35-7.57(m, 6H), 7.77 (dd, 1H), 7.94 (d, 1H), 8.20 (s, 1H), 8.42 (s, 1H), 8.50(d, 1H), 8.70 (s, 2H), 9.28 (s, 1H).

Example 15-1441-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.59 (Methylene chloride:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 2.04 (s, 3H), 5.86 (brs, 2H), 7.16-7.46 (m, 9H),7.50 (d, 2H), 7.72 (s, 1H), 7.95 (d, 1H), 8.53 (s, 1H), 8.65 (s, 2H),9.45 (s, 1H).

Example 15-1451-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.56 (Methylene chloride:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 2.04 (s, 3H), 5.56 (brs, 2H), 7.16-7.48 (m, 9H),7.52 (d, 2H), 7.72 (s, 1H), 7.93 (d, 1H), 8.53 (s, 1H), 8.65 (s, 2H),9.45 (s, 1H).

Example 15-1461-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2′-ethyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.51 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 0.99 (t, 3H), 2.21-2.50 (m, 2H), 5.85 (s, 2H), 7.16(d, 1H), 7.15-7.51 (m, 10H), 7.66 (s, 1H), 7.94 (d, 1H), 8.53 (s, 1H),8.64 (s, 2H), 9.47 (s, 1H).

Example 15-1471-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2′-ethyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.50 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 0.99 (t, 3H), 2.21-2.50 (m, 2H), 5.56 (s, 2H), 7.16(d, 1H), 7.22-7.56 (m, 10H), 7.66 (s, 1H), 7.93 (d, 1H), 8.53 (s, 1H),8.64 (s, 2H), 9.47 (s, 1H).

Example 15-1481-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{5-chloro-2-[4-(difluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

TLC:Rf 0.16 (Hexane:Ethyl Acetate:Methanol=6:4:0.4);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.13 (t, 1H), 7.20-7.29 (m, 3H), 7.36(dd, 1H), 7.46-7.57 (m, 3H), 7.92 (d, 1H), 8.11 (s, 1H), 8.23 (d, 1H),8.58 (s, 1H), 8.67 (s, 2H), 8.90 (s, 1H) 9.77 (s, 1H).

Example 15-1491-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{5-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

TLC:Rf 0.20 (Hexane:Ethyl Acetate:Methanol=6:4:0.4);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.07 (s, 1H), 7.20-7.32 (m, 3H), 7.37(dd, 1H), 7.43-7.57 (m, 3H), 7.92 (d, 1H), 8.18 (s, 1H), 8.37 (s, 2H),8.65 (s, 2H), 9.43 (s, 1H).

Example 15-1501-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-chloro-2-(4-fluoro-1H-pyrazol-1-yl)phenyl]urea

TLC:Rf 0.45 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.19-7.30 (m, 3H), 7.38-7.54 (m, 4H),7.91-7.99 (m, 2H), 8.24 (d, 1H), 8.42 (d, 1H), 8.69 (s, 2H), 8.94 (s,1H), 9.76 (s, 1H).

Example 15-1511-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-chloro-2-(4-fluoro-1H-pyrazol-1-yl)phenyl]urea

TLC:Rf 0.39 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.19-7.30 (m, 3H), 7.36 (dd, 1H), 7.44(d, 1H), 7.51 (d, 2H), 7.92 (d, 1H), 7.95 (d, 1H), 8.24 (d, 1H), 8.42(d, 1H), 8.68 (s, 2H), 8.94 (s, 1H), 9.75 (s, 1H).

Example 15-1521-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4′-ethyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.31 (Hexane:Ethyl Acetate=2:3);

¹H-NMR (DMSO-d₆): δ 1.24 (t, 3H), 2.69 (q, 2H), 5.57 (s, 2H), 7.24-7.31(m, 2H), 7.34-7.56 (m, 9H), 7.93 (d, 1H), 8.09 (s, 1H), 8.41 (s, 1H),8.67 (s, 2H), 9.41 (s, 1H).

Example 15-1531-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-fluoro-2-(3-pyridinyl)phenyl]urea

TLC:Rf 0.51 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.02 (dt, 1H), 7.24-7.31 (m, 3H), 7.42(d, 1H), 7.49-7.55 (m, 3H), 7.82 (dt, 1H), 7.88 (dd, 1H), 7.95 (d, 1H),8.12 (s, 1H), 8.58-8.65 (m, 4H), 9.23 (s, 1H).

Example 15-1541-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3,4-bis(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.99 minutes);

MASS (ESI, Pos.): 569 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.87 (s, 2H), 7.25-7.31 (m, 2H), 7.43 (d, 1H),7.49-7.55 (m, 2H), 7.86-7.98 (m, 3H), 8.20 (s, 1H), 8.74 (s, 2H), 9.16(s, 1H), 9.77 (s, 1H).

Example 15-1551-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-methyl-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.94 minutes);

MASS (ESI, Pos.): 515 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.39 (s, 3H), 5.87 (s, 2H), 7.25-7.32 (m, 2H),7.42-7.61 (m, 6H), 7.95 (d, 1H), 8.73 (s, 2H), 8.98 (s, 1H), 9.28 (s,1H).

Example 15-1561-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-fluoro-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.93 minutes);

MASS (ESI, Pos.): 519 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.87 (s, 2H), 7.25-7.32 (m, 2H), 7.33-7.39 (m, 1H),7.43 (d, 1H), 7.48-7.51 (m, 2H), 7.63-7.74 (m, 2H), 7.96 (d, 1H), 8.73(s, 2H), 9.10 (s, 1H), 9.62 (s, 1H).

Example 15-1571-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-fluoro-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.90 minutes);

MASS (ESI, Pos.): 531 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.84 (s, 3H), 5.86 (s, 2H), 7.07-7.15 (m, 1H),7.25-7.32 (m, 2H), 7.41-7.56 (m, 5H), 7.95 (d, 1H), 8.73 (s, 2H), 8.98(s, 1H), 9.38 (s, 1H).

Example 15-1581-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2,3-difluoro-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.95 minutes);

MASS (ESI, Pos.): 537 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.25-7.32 (m, 2H), 7.43 (d, 1H),7.48-7.61 (m, 3H), 7.94-7.98 (m, 1H), 8.13-8.21 (m, 1H), 8.75 (s, 2H),9.36 (s, 2H).

Example 15-1591-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-methoxy-3-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 531 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.84 (s, 3H), 5.87 (s, 2H), 7.19-7.31 (m, 3H), 7.43(d, 1H), 7.49-7.54 (m, 2H), 7.60 (dd, 1H), 7.80 (d, 1H), 7.95 (d, 1H),8.71 (s, 2H), 8.90 (s, 1H), 9.03 (s, 1H).

Example 15-1601-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-methoxy-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.91 minutes);

MASS (ESI, Pos.): 531 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.80 (s, 3H), 5.87 (s, 2H), 6.83-6.90 (m, 1H),7.24-7.31 (m, 3H), 7.41-7.45 (m, 1H), 7.46-7.55 (m, 3H), 7.94-7.97 (m,1H), 8.72 (s, 2H), 8.98 (s, 1H), 9.31 (s, 1H).

Example 15-1611-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3,4-bis(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.92 minutes);

MASS (ESI, Pos.): 553 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.58 (s, 2H), 7.25-7.33 (m, 2H), 7.38 (dd, 1H),7.51-7.58 (m, 2H), 7.85-7.99 (m, 3H), 8.19-8.23 (m, 1H), 8.74 (s, 2H),9.17 (s, 1H), 9.78 (s, 1H).

Example 15-1621-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-methyl-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 499 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.40 (s, 3H), 5.58 (s, 2H), 7.25-7.60 (m, 8H),7.94-7.96 (m, 1H), 8.73 (s, 2H), 8.98 (s, 1H), 9.28 (s, 1H).

Example 15-1631-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-fluoro-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.86 minutes);

MASS (ESI, Pos.): 503 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.58 (s, 2H), 7.25-7.43 (m, 4H), 7.50-7.58 (m, 2H),7.63-7.75 (m, 2H), 7.94 (d, 1H), 8.73 (s, 2H), 9.10 (s, 1H), 9.61 (s,1H).

Example 15-1641-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-methoxy-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 515 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.97 (s, 3H), 5.57 (s, 2H), 7.25-7.57 (m, 7H), 7.94(d, 1H), 8.29-8.36 (m, 1H), 8.69-8.75 (m, 3H), 9.66 (s, 1H).

Example 15-1651-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-methoxy-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.83 minutes);

MASS (ESI, Pos.): 515 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.83 (s, 3H), 5.57 (s, 2H), 7.07-7.14 (m, 1H),7.25-7.32 (m, 2H), 7.35-7.57 (m, 5H), 7.93 (d, 1H), 8.72 (s, 2H), 8.97(s, 1H), 9.37 (s, 1H).

Example 15-1661-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-fluoro-3-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 88% (Retention Time: 0.83 minutes);

MASS (ESI, Pos.): 503 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.58 (s, 2H), 7.25-7.32 (m, 2H), 7.35-7.58 (m, 4H),7.65-7.75 (m, 1H), 7.92-8.00 (m, 2H), 8.72 (s, 2H), 9.01 (s, 1H), 9.31(s, 1H).

Example 15-1671-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-methoxy-3-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.80 minutes);

MASS (ESI, Pos.): 515 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.84 (s, 3H), 5.58 (s, 2H), 7.19-7.31 (m, 3H), 7.38(dd, 1H), 7.50-7.57 (m, 2H), 7.58-7.65 (m, 1H), 7.78-7.83 (m, 1H),7.93-7.96 (m, 1H), 8.72 (s, 2H), 8.90 (s, 1H), 9.03 (s, 1H).

Example 15-1681-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-methoxy-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.84 minutes);

MASS (ESI, Pos.): 515 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.80 (s, 3H), 5.57 (s, 2H), 6.86 (s, 1H), 7.25-7.58(m, 7H), 7.94 (d, 1H), 8.72 (s, 2H), 8.98 (s, 1H), 9.31 (s, 1H).

Example 15-1691-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2,6-difluoro-3-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.84 minutes);

MASS (ESI, Pos.): 537 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.24-7.30 (m, 2H), 7.37-7.55 (m, 4H),7.71-7.82 (m, 1H), 7.95 (d, 1H), 8.67 (brs, 1H), 8.72 (s, 2H), 9.38(brs, 1H).

Example 15-1701-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2,6-difluoro-3-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.77 minutes);

MASS (ESI, Pos.): 521 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 7.24-7.31 (m, 2H), 7.35-7.56 (m, 4H),7.71-7.82 (m, 1H), 7.92-7.96 (m, 1H), 8.66 (s, 1H), 8.72 (s, 2H), 9.37(s, 1H).

Example 15-1711-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3,5-bis(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.00 minute);

MASS (ESI, Pos.): 569 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.87 (s, 2H), 7.25-7.31 (m, 2H), 7.42-7.45 (m, 1H),7.49-7.55 (m, 2H), 7.65-7.70 (m, 1H), 7.95-7.98 (m, 1H), 8.15 (s, 2H),8.74 (s, 2H), 9.21 (s, 1H), 9.68 (s, 1H).

Example 15-1721-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3,5-bis(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.89 minutes);

MASS (ESI, Pos.): 485 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.05-7.13 (m, 1H), 7.25-7.37 (m, 3H),7.43 (d, 1H), 7.48-7.56 (m, 2H), 7.95 (d, 1H), 8.20 (dd, 1H), 8.74 (s,2H), 8.97 (s, 1H), 9.28 (s, 1H).

Example 15-1731-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3,5-bis(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.96 minutes);

MASS (ESI, Pos.): 501 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.20 (t, 1H), 7.25-7.31 (m, 2H), 7.43(d, 1H), 7.49-7.56 (m, 4H), 7.95 (d, 1H), 8.72 (s, 2H), 9.09 (s, 1H),9.33 (s, 1H).

Example 15-1741-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(3-chloro-5-methylphenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.91 minutes);

MASS (ESI, Pos.): 481 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.32 (s, 3H), 5.86 (s, 2H), 6.86-6.90 (s, 1H),7.10-7.15 (m, 1H), 7.24-7.31 (m, 2H), 7.42-7.55 (m, 4H), 7.95 (d, 1H),8.72 (s, 2H), 8.92 (s, 1H), 9.06 (s, 1H).

Example 15-1751-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(3-chloro-5-fluorophenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.90 minutes);

MASS (ESI, Pos.): 485 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 6.98-7.06 (m, 1H), 7.25-7.55 (m, 7H),7.95 (d, 1H), 8.72 (s, 2H), 9.06 (s, 1H), 9.36 (s, 1H).

Example 15-1761-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(5-chloro-2-methoxyphenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.90 minutes);

MASS (ESI, Pos.): 497 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.88 (s, 3H), 5.86 (s, 2H), 6.98-7.08 (m, 2H),7.25-7.32 (m, 2H), 7.43 (d, 1H), 7.49-7.55 (m, 2H), 7.95 (d, 1H), 8.18(d, 1H), 8.56 (s, 1H), 8.72 (s, 2H), 9.59 (s, 1H).

Example 15-1771-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(3-chloro-5-methoxyphenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 497 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.74 (s, 3H), 5.86 (s, 2H), 6.60-6.66 (m, 1H),6.95-7.00 (m, 1H), 7.15-7.20 (m, 1H), 7.24-7.30 (m, 2H), 7.43 (d, 1H),7.45-7.55 (m, 2H), 7.95 (d, 1H), 8.71 (s, 2H), 8.93 (s, 1H), 9.13 (s,1H).

Example 15-1781-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-chloro-2-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.94 minutes);

MASS (ESI, Pos.): 535 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.25-7.31 (m, 2H), 7.34-7.40 (m, 1H),7.43 (d, 1H), 7.49-7.55 (m, 2H), 7.72 (d, 1H), 7.95 (d, 1H), 8.10-8.14(m, 1H), 8.42 (brs, 1H), 8.74 (s, 2H), 9.67 (brs, 1H).

Example 15-1791-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(2,3-dichlorophenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.91 minutes);

MASS (ESI, Pos.): 501 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.25-7.55 (m, 7H), 7.96 (d, 1H),8.08-8.15 (m, 1H), 8.66 (s, 1H), 8.74 (s, 2H), 9.65 (s, 1H).

Example 15-1801-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(4-chloro-2-methoxyphenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.89 minutes);

MASS (ESI, Pos.): 497 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.90 (s, 3H), 5.86 (s, 2H), 6.96 (dd, 1H), 7.10 (d,1H), 7.25-7.31 (m, 2H), 7.42 (d, 1H), 7.48-7.55 (m, 2H), 7.95 (d, 1H),8.09 (d, 1H), 8.45 (s, 1H), 8.71 (s, 2H), 9.52 (s, 1H).

Example 15-1811-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(4-chloro-2-methylphenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 481 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.23 (s, 3H), 5.86 (s, 2H), 7.18-7.31 (m, 4H), 7.42(d, 1H), 7.48-7.55 (m, 2H), 7.80 (d, 1H), 7.95 (d, 1H), 8.22 (s, 1H),8.72 (s, 2H), 9.21 (s, 1H).

Example 15-1821-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(4-chloro-2-fluorophenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 485 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.20-7.55 (m, 7H), 7.95 (d, 1H), 8.09(t, 1H), 8.73 (s, 2H), 8.56 (s, 1H), 9.22 (s, 1H).

Example 15-1831-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-chloro-2-(methylsulfonyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.85 minutes);

MASS (ESI, Pos.): 545 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.36 (s, 3H), 5.86 (s, 2H), 7.25-7.32 (m, 2H), 7.43(d, 1H), 7.49-7.56 (m, 2H), 7.75-7.84 (m, 2H), 7.96 (d, 1H), 8.21 (d,1H), 8.74 (s, 2H), 8.79 (s, 1H), 10.18 (s, 1H).

Example 15-1841-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-chloro-3-(methylsulfonyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.75 minutes);

MASS (ESI, Pos.): 545 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.35 (s, 3H), 5.87 (s, 2H), 7.25-7.32 (m, 2H), 7.43(d, 1H), 7.49-7.55 (m, 2H), 7.63 (d, 1H), 7.78 (dd, 1H), 7.95-7.96 (m,1H), 8.27 (d, 1H), 8.73 (s, 2H), 9.00 (s, 1H), 9.56 (s, 1H).

Example 15-1851-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-chloro-2-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.93 minutes);

MASS (ESI, Pos.): 535 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.25-7.31 (m, 2H), 7.42-7.45 (m, 1H),7.49-7.55 (m, 2H), 7.71-7.79 (m, 2H), 7.95-8.01 (m, 2H), 8.38 (s, 1H),8.74 (s, 2H), 9.57 (s, 1H).

Example 15-1861-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(2,3-dihydro-1H-inden-5-yl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.49 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.00-2.10 (m, 2H), 2.93 (t, 4H), 5.85 (s, 2H), 7.17(dd, 1H), 7.25-7.27 (m, 3H), 7.37-7.44 (m, 4H), 7.50 (d, 2H), 7.95 (d,1H), 8.04 (s, 1H), 8.45 (s, 1H), 8.67 (s, 2H), 9.45 (s, 1H).

Example 15-1871-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(2,3-dihydro-1H-inden-5-yl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.44 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.00-2.10 (m, 2H), 2.93 (t, 4H), 5.57 (s, 2H), 7.16(dd, 1H), 7.25-7.28 (m, 3H), 7.35-7.44 (m, 4H), 7.52 (d, 2H), 7.93 (d,1H), 8.04 (s, 1H), 8.45 (s, 1H), 8.67 (s, 2H), 9.45 (s, 1H).

Example 15-1881-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(2,3-dihydro-1-benzofuran-5-yl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.28 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 3.25 (t, 2H), 4.60 (t, 2H), 5.85 (s, 2H), 6.91 (d,1H), 7.14 (dd, 1H), 7.24-7.29 (m, 3H), 7.37-7.42 (m, 3H), 7.50 (d, 2H),7.95 (d, 1H), 8.03 (s, 1H), 8.44 (s, 1H), 8.67 (s, 2H), 9.45 (s, 1H).

Example 15-1891-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(2,3-dihydro-1-benzofuran-5-yl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.24 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 3.25 (t, 2H), 4.60 (t, 2H), 5.57 (s, 2H), 6.91 (d,1H), 7.14 (dd, 1H), 7.25-7.29 (m, 3H), 7.35-7.42 (m, 3H), 7.53 (d, 2H),7.94 (d, 1H), 8.03 (s, 1H), 8.45 (s, 1H), 8.68 (s, 2H), 9.45 (s, 1H).

Example 15-1901-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{5-(difluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

TLC:Rf 0.40 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.08 (d, 1H), 7.13 (t, 1H), 7.26 (d,2H), 7.32-7.45 (m, 2H), 7.51 (d, 2H), 7.60 (d, 1H), 7.92 (d, 1H), 8.28(s, 1H), 8.41 (s, 1H), 8.45 (s, 1H), 8.65 (s, 2H), 9.42 (s, 1H).

Example 15-1911-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{4-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

TLC:Rf 0.45 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.06 (d, 1H), 7.25 (d, 2H), 7.36 (dd,1H), 7.49-7.62 (m, 4H), 7.92 (d, 1H), 8.02 (d, 1H), 8.35 (s, 1H),8.38-8.42 (m, 1H), 8.64 (s, 2H), 9.36 (s, 1H).

Example 15-1921-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2,3-difluoro-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 93% (Retention Time: 0.89 minutes);

MASS (ESI, Pos.): 521 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.57 (s, 2H), 7.26-7.33 (m, 2H), 7.38 (dd, 1H),7.51-7.62 (m, 3H), 7.94 (d, 1H), 8.13-8.22 (m, 1H), 8.75 (s, 2H), 9.36(s, 2H).

Example 15-1931-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.00 minute);

MASS (ESI, Pos.): 553 (M+H)⁺.

Example 15-1941-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(5-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.89 minutes);

MASS (ESI, Pos.): 626 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.38 (s, 3H), 6.48 (s, 2H), 7.24-8.54 (m, 13H), 8.66(s, 2H), 9.29 (s, 1H).

Example 15-1951-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.09 minutes);

MASS (ESI, Pos.): 611 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.48 (s, 2H), 7.25-7.31 (m, 2H), 7.40-7.59 (m, 10H),8.09 (s, 1H), 8.26-8.30 (m, 1H), 8.40-8.44 (m, 1H), 8.66 (s, 2H), 9.40(s, 1H).

Example 15-1961-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[5-phenyl-2-(trifluoromethyl)-4-pyridinyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.02 minutes);

MASS (ESI, Pos.): 612 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.48 (s, 2H), 7.26-7.32 (m, 2H), 7.49-7.66 (m, 8H),8.27-8.30 (m, 1H), 8.42-8.46 (m, 2H), 8.69 (s, 2H), 8.75 (s, 1H), 9.74(s, 1H).

Example 15-1971-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-phenyl-5-(trifluoromethyl)-3-pyridinyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 612 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.48 (s, 2H), 7.25-7.32 (m, 2H), 7.49-7.70 (m, 8H),8.26-8.30 (m, 1H), 8.43 (s, 1H), 8.68 (s, 2H), 8.74-8.75 (m, 1H),8.76-8.78 (m, 1H), 9.47 (s, 1H).

Example 15-1981-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[3′,4′-dimethyl-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.17 minutes);

MASS (ESI, Pos.): 639 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.29 (s, 6H), 6.48 (s, 2H), 7.12-7.58 (m, 10H), 8.01(s, 1H), 8.26-8.30 (m, 1H), 8.45-8.48 (m, 1H), 8.67 (s, 2H), 9.46 (s,1H).

Example 15-1991-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(6-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 98% (Retention Time: 0.84 minutes);

MASS (ESI, Pos.): 626 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.55 (s, 3H), 6.48 (s, 2H), 7.25-7.32 (m, 2H),7.39-7.59 (m, 6H), 7.75-7.80 (m, 1H), 8.19-8.23 (m, 1H), 8.26-8.30 (m,1H), 8.41-8.44 (m, 1H), 8.49-8.53 (m, 1H), 8.67 (s, 2H), 9.28 (s, 1H).

Example 15-2001-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[3-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.96 minutes);

MASS (ESI, Pos.): 535 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.49 (s, 2H), 7.26-7.36 (m, 3H), 7.48-7.66 (m, 5H),7.96-8.00 (m, 1H), 8.27-8.30 (m, 1H), 8.73 (s, 2H), 8.99 (s, 1H), 9.33(s, 1H).

Example 15-2011-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-fluoro-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.00 minute);

MASS (ESI, Pos.): 553 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.49 (s, 2H), 7.26-7.34 (m, 2H), 7.49-7.59 (m, 4H),7.72 (dd, 1H), 8.26-8.31 (m, 1H), 8.37 (t, 1H), 8.75 (s, 2H), 9.14 (s,1H), 9.34 (s, 1H).

Example 15-2021-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-fluoro-4-(trifluoromethyl)phenyl]urea

TLC:Rf 0.28 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 1.20 (t, 3H), 2.68 (q, 2H), 5.57 (s, 2H), 7.25-7.46(m, 5H), 7.51-7.58 (m, 2H), 7.94 (d, 1H), 8.25 (s, 1H), 8.38 (s, 1H),8.75 (s, 2H), 9.34 (s, 1H).

Example 15-2031-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(6-ethyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.34 (Methylene Chloride:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 1.29 (t, 3H), 2.84 (q, 2H), 5.86 (brs, 2H), 7.26 (d,2H), 7.39-7.54 (m, 6H), 7.80 (dd, 1H), 7.95 (d, 1H), 8.24 (s, 1H), 8.40(s, 1H), 8.54 (d, 1H), 8.67 (s, 2H), 9.26 (s, 1H).

Example 15-2041-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(6-ethyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.34 (Methylene Chloride:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 1.29 (t, 3H), 2.84 (q, 2H), 5.58 (brs, 2H), 7.26 (d,2H), 7.37 (dd, 1H), 7.41-7.55 (m, 5H), 7.80 (dd, 1H), 7.94 (d, 1H), 8.24(s, 1H), 8.40 (s, 1H), 8.54 (d, 1H), 8.67 (s, 2H), 9.26 (s, 1H).

Example 15-2051-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(5-ethyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.33 (Methylene Chloride:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 1.23 (t, 3H), 2.70 (q, 2H), 5.86 (brs, 2H), 7.26 (d,2H), 7.42 (d, 1H), 7.45-7.55 (m, 4H), 7.73 (s, 1H), 7.95 (dd, 1H), 8.23(s, 1H), 8.38 (s, 1H), 8.47 (d, 1H), 8.54 (d, 1H), 8.65 (s, 2H), 9.27(s, 1H).

Example 15-2061-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(5-ethyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.33 (Methylene Chloride:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 1.23 (t, 3H), 2.70 (q, 2H), 5.57 (brs, 2H), 7.26 (d,2H), 7.37 (dd, 1H), 7.47-7.56 (m, 4H), 7.73 (t, 1H), 7.93 (d, 1H), 8.23(s, 1H), 8.38 (s, 1H), 8.47 (d, 1H), 8.54 (d, 1H), 8.65 (s, 2H), 9.27(s, 1H).

Example 15-2071-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-isopropyl-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.38 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 1.22 (d, 6H), 3.14-3.27 (m, 1H), 5.57 (s, 2H),7.26-7.33 (m, 2H), 7.36-7.57 (m, 5H), 7.94 (d, 1H), 8.12-8.15 (m, 1H),8.43 (s, 1H), 8.74 (s, 2H), 9.28 (s, 1H).

Example 15-2081-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-4-(trifluoromethyl)phenyl]urea

TLC:Rf 0.62 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 3.42 (s, 3H), 5.58 (s, 2H), 7.27-7.34 (m, 2H), 7.38(dd, 1H), 7.52-7.60 (m, 2H), 7.94 (d, 1H), 8.05-8.12 (m, 2H), 8.46-8.56(m, 1H), 8.76 (s, 2H), 9.04 (s, 1H), 10.36 (s, 1H).

Example 15-2091-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(4-cyano-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.20 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.26 (d, 2H), 7.41 (dd, 1H), 7.50 (d,2H), 7.58 (d, 1H), 7.73 (d, 1H), 7.94 (dd, 1H), 8.52 (s, 1H), 8.54 (s,1H), 8.69 (s, 2H), 8.80 (s, 1H), 9.13 (s, 1H), 9.63 (s, 1H).

Example 15-2101-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(4-cyano-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.16 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.56 (s, 2H), 7.26 (d, 2H), 7.37 (dd, 1H), 7.52 (d,2H), 7.58 (d, 1H), 7.73 (d, 1H), 7.92 (d, 1H), 8.52 (s, 1H), 8.54 (s,1H), 8.68 (s, 2H), 8.80 (s, 1H), 9.13 (s, 1H), 9.63 (s, 1H).

Example 15-2111-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-phenylurea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.77 minutes);

MASS (ESI, Pos.): 433 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 6.98 (t, 1H), 7.23-7.32 (m, 4H),7.41-7.55 (m, 5H), 7.95 (dd, 1H), 8.72 (s, 2H), 8.85 (s, 1H), 8.93 (s,1H).

Example 15-2121-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-(trifluoromethyl)-2-thienyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.90 minutes);

MASS (ESI, Pos.): 507 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 6.62-6.66 (m, 1H), 7.25-7.32 (m, 2H),7.38-7.45 (m, 2H), 7.49-7.55 (m, 2H), 7.95 (d, 1H), 8.72 (s, 2H), 9.23(s, 1H), 10.60 (s, 1H).

Example 15-2131-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(4-morpholinyl)-3-pyridinyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.71 minutes);

MASS (ESI, Pos.): 519 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.96-3.03 (m, 4H), 3.80-3.86 (m, 4H), 5.86 (s, 2H),7.08 (dd, 1H), 7.25-7.32 (m, 2H), 7.43 (d, 1H), 7.48-7.55 (m, 2H),7.95-8.02 (m, 2H), 8.14 (s, 1H), 8.28 (dd, 1H), 8.74 (s, 2H), 9.71 (s,1H).

Example 15-2141-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(2,3-dihydro-1-benzofuran-7-yl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.80 minutes);

MASS (ESI, Pos.): 475 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.22 (t, 2H), 4.60 (t, 2H), 5.86 (s, 2H), 6.76 (t,1H), 6.89 (d, 1H), 7.24-7.30 (m, 2H), 7.42 (d, 1H), 7.49-7.55 (m, 2H),7.77 (d, 1H), 7.95-7.98 (m, 1H), 8.35 (s, 1H), 8.71 (s, 2H), 9.24 (s,1H).

Example 15-2151-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(2,3-dihydro-1-benzofuran-5-yl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.75 minutes);

MASS (ESI, Pos.): 475 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.14 (t, 2H), 4.47 (t, 2H), 5.86 (s, 2H), 6.67 (d,1H), 7.06 (dd, 1H), 7.24-7.29 (m, 2H), 7.34-7.38 (m, 1H), 7.42-7.44 (m,1H), 7.48-7.55 (m, 2H), 7.95-7.98 (m, 1H), 8.65-8.97 (m, 4H).

Example 15-2162-[({2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}carbamoyl)amino]-N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide

TLC:Rf 0.57 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 2.76 (s, 6H), 5.57 (s, 2H), 7.26-7.32 (m, 2H), 7.38(dd, 1H), 7.51-7.64 (m, 3H), 7.92-7.98 (m, 2H), 8.61 (s, 1H), 8.74 (s,2H), 8.99 (s, 1H), 10.31 (s, 1H).

Example 15-2171-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)phenyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 0.76 minutes);

MASS (ESI, Pos.): 511 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.28 (s, 3H), 5.87 (s, 2H), 7.26-7.34 (m, 3H),7.42-7.45 (m, 1H), 7.49-7.55 (m, 2H), 7.66-7.73 (m, 1H), 7.85 (dd, 1H),7.95-7.98 (m, 1H), 8.15 (d, 1H), 8.75 (s, 2H), 8.77 (s, 1H), 10.13 (s,1H).

Example 15-2181-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.69 minutes);

MASS (ESI, Pos.): 495 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.28 (s, 3H), 5.57 (s, 2H), 7.25-7.34 (m, 3H), 7.38(dd, 1H), 7.51-7.57 (m, 2H), 7.69 (td, 1H), 7.85 (dd, 1H), 7.94 (d, 1H),8.15 (d, 1H), 8.75 (s, 2H), 8.77 (s, 1H), 10.13 (s, 1H).

Example 15-2191-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.85 minutes);

MASS (ESI, Pos.): 545 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.28 (s, 3H), 6.49 (s, 2H), 7.26-7.33 (m, 3H),7.50-7.59 (m, 3H), 7.69 (td, 1H), 7.85 (dd, 1H), 8.15 (d, 1H), 8.26-8.30(m, 1H), 8.75-8.81 (m, 3H), 10.13 (s, 1H).

Example 15-2201-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(5-chloro-2-methylphenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.82 minutes);

MASS (ESI, Pos.): 465 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.22 (s, 3H), 5.57 (s, 2H), 7.00 (dd, 1H), 7.20 (d,1H), 7.28 (d, 2H), 7.38 (dd, 1H), 7.52 (d, 2H), 7.93 (d, 1H), 7.97 (d,1H), 8.26 (s, 1H), 8.74 (s, 2H), 9.30 (s, 1H).

Example 15-2211-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[3′-(hydroxymethyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 641 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.58 (d, 2H), 5.28 (t, 1H), 6.48 (s, 2H), 7.22-7.58(m, 11H), 8.06 (s, 1H), 8.27 (s, 1H), 8.42 (s, 1H), 8.66 (s, 2H), 9.42(s, 1H).

Example 15-2221-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-{5-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.06 minutes);

MASS (ESI, Pos.): 635 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 6.48 (s, 2H), 7.08 (d, 1H), 7.22-7.35 (m, 3H),7.43-7.59 (m, 4H), 8.18 (d, 1H), 8.23-8.29 (m, 1H), 8.36-8.42 (m, 2H),8.66 (s, 2H), 9.44 (s, 1H).

Example 15-2232-{[(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)carbamoyl]amino}-N-methyl-4-(trifluoromethyl)benzenesulfonamide

TLC:Rf 0.36 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 3.27-3.38 (m, 3H), 6.49 (s, 2H), 7.27-7.34 (m, 2H),7.49-7.63 (m, 4H), 7.93-7.99 (m, 1H), 8.02-8.13 (m, 1H), 8.28 (s, 1H),8.56 (s, 1H), 8.75 (s, 2H), 8.90 (s, 1H), 10.23 (s, 1H).

Example 15-2242-[({2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}carbamoyl)amino]-N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 0.98 minutes);

MASS (ESI, Pos.): 608 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.76 (s, 6H), 5.87 (s, 2H), 7.28 (d, 2H), 7.43 (d,1H), 7.52 (d, 2H), 7.60 (d, 1H), 7.92-7.98 (m, 2H), 8.61 (s, 1H), 8.75(s, 2H), 8.99 (s, 1H), 10.31 (s, 1H).

Example 15-2251-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[5-methyl-2-(methylsulfonyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.92 minutes);

MASS (ESI, Pos.): 559 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.37 (s, 3H), 3.24 (s, 3H), 6.49 (s, 2H), 7.12 (d,1H), 7.28 (d, 2H), 7.52 (d, 2H), 7.55 (d, 1H), 7.73 (d, 1H), 7.99 (s,1H), 8.26-8.29 (m, 1H), 8.72 (s, 1H), 8.75 (s, 2H), 10.12 (s, 1H).

Example 15-2261-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[5-chloro-2-(methylsulfonyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.97 minutes);

MASS (ESI, Pos.): 579 (M+H)⁺.

Example 15-2271-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-fluoro-2-(methylsulfonyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.85 minutes);

MASS (ESI, Pos.): 529 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.15 (d, 3H), 5.87 (s, 2H), 7.10-7.19 (m, 1H), 7.28(d, 2H), 7.43 (d, 1H), 7.52 (d, 2H), 7.92 (dd, 1H), 7.96 (d, 1H), 8.11(dd, 1H), 8.75 (s, 2H), 8.95 (s, 1H), 10.29 (s, 1H).

Example 15-2281-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(methylthio)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.30 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.53 (s, 3H), 6.47 (s, 2H), 7.27 (d, 2H), 7.40 (dd,1H), 7.48-7.57 (m, 4H), 8.18 (s, 1H), 8.24-8.28 (m, 1H), 8.44 (s, 1H),8.73 (s, 2H), 9.64 (s, 1H).

Example 15-2291-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-fluoro-3-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.94 minutes);

MASS (ESI, Pos.): 519 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 5.86 (s, 2H), 7.27 (d, 2H), 7.40-7.57 (m, 4H),7.64-7.72 (m, 1H), 7.94-7.99 (m, 2H), 8.73 (s, 2H), 9.03 (s, 1H), 9.33(s, 1H).

Example 15-2301-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[3′-(1-hydroxyethyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.05 minutes);

MASS (ESI, Pos.): 655 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.36 (d, 3H), 4.79 (quint, 1H), 5.20 (d, 1H), 6.48(s, 2H), 7.27 (d, 2H), 7.27-7.35 (m, 1H), 7.39-7.58 (m, 8H), 8.09 (s,1H), 8.27 (d, 1H), 8.37 (s, 1H), 8.66 (s, 2H), 9.40 (s, 1H).

Example 15-2311-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[5-chloro-2-(methylthio)phenyl]urea

TLC:Rf 0.55 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.42 (s, 3H), 6.48 (s, 2H), 7.08-7.14 (m, 1H), 7.27(d, 2H), 7.43 (d, 1H), 7.51 (d, 2H), 7.55 (d, 1H), 8.06 (d, 1H),8.25-8.28 (m, 1H), 8.48 (s, 1H), 8.73 (s, 2H), 9.76 (s, 1H).

Example 15-2321-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-chloro-2-(methylthio)phenyl]urea

TLC:Rf 0.42 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.42 (s, 3H), 5.57 (s, 2H), 7.10 (dd, 1H), 7.27 (d,2H), 7.37 (dd, 1H), 7.43 (d, 1H), 7.52 (d, 2H), 7.93 (d, 1H), 8.06 (d,1H), 8.48 (s, 1H), 8.73 (s, 2H), 9.76 (s, 1H).

Example 15-2331-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-chloro-2-(methylsulfinyl)phenyl]urea

TLC:Rf 0.61 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 2.85 (s, 3H), 6.48 (s, 2H), 7.27 (d, 2H), 7.32-7.41(m, 2H), 7.53 (d, 2H), 7.67 (d, 1H), 7.93 (d, 1H), 8.00 (d, 1H), 8.73(s, 2H), 9.23 (s, 1H), 9.69 (s, 1H).

Example 15-2341-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.02 minutes);

MASS (ESI, Pos.): 615 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.65 (s, 3H), 6.48 (s, 2H), 7.27 (d, 2H), 7.46-7.61(m, 6H), 7.62 (d, 1H), 8.10 (s, 1H), 8.27 (d, 1H), 8.56 (s, 1H), 8.68(s, 2H), 9.50 (s, 1H).

Example 15-2352-[({2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}carbamoyl)amino]-N-ethyl-N-methyl-4-(trifluoromethyl)benzenesulfonamide

TLC:Rf 0.65 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 1.04 (t, 3H), 2.80 (s, 3H), 3.20 (q, 2H), 5.85 (s,2H), 7.26-7.32 (m, 2H), 7.43 (d, 1H), 7.50-7.55 (m, 2H), 7.57-7.62 (m,1H), 7.94-8.01 (m, 2H), 8.54-8.58 (m, 1H), 8.75 (s, 2H), 8.92 (s, 1H),10.30 (s, 1H).

Example 15-2361-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(tetrahydro-2H-pyran-4-yl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.65 minutes);

MASS (ESI, Pos.): 441 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.32-1.50 (m, 2H), 1.71-1.83 (m, 2H), 3.32-3.42 (m,2H), 3.60-3.89 (m, 3H), 5.85 (s, 2H), 6.48 (d, 1H), 7.22-7.28 (m, 2H),7.42 (d, 1H), 7.47-7.54 (m, 2H), 7.95 (d, 1H), 8.54 (s, 1H), 8.65 (s,2H).

Example 15-237rel-1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 495 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 0.70-1.15 (m, 12H), 1.32-2.04 (m, 6H), 3.31-3.50 (m,1H), 5.85 (s, 2H), 6.21 (d, 1H), 7.21-7.28 (m, 2H), 7.42 (d, 1H),7.47-7.54 (m, 2H), 7.95 (d, 1H), 8.48 (s, 1H), 8.65-8.69 (m, 2H).

Example 15-2381-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(2-hydroxycyclohexyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.67 minutes);

MASS (ESI, Pos.): 455 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.00-1.35 (m, 4H), 1.45-1.70 (m, 2H), 1.78-1.97 (m,2H), 3.15-3.38 (m, 2H), 4.68 (d, 1H), 5.85 (s, 2H), 6.28 (d, 1H),7.22-7.28 (m, 2H), 7.41 (d, 1H), 7.47-7.54 (m, 2H), 7.94-7.98 (m, 1H),8.62-8.69 (m, 3H).

Example 15-2391-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-(2-hydroxycyclohexyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.65 minutes);

MASS (ESI, Pos.): 455 (M+H)⁺.

Example 15-2402-[({2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}carbamoyl)amino]-N,N-diethyl-4-(trifluoromethyl)benzenesulfonamide

TLC:Rf 0.45 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.03 (s, 6H), 3.30 (q, 4H), 5.87 (s, 2H), 7.25-7.31(m, 2H), 7.43 (d, 1H), 7.49-7.56 (m, 2H), 7.58 (dd, 1H), 7.96 (d, 1H),8.00 (d, 1H), 8.49 (d, 1H), 8.75 (s, 2H), 8.84 (s, 1H), 10.30 (s, 1H).

Example 15-2411-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[5-chloro-2-(4-cyano-1H-pyrazol-1-yl)phenyl]urea

TLC:Rf 0.40 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 5.85 (s, 2H), 7.23-7.32 (m, 3H), 7.42 (d, 1H),7.47-7.54 (m, 3H), 7.95 (d, 1H), 8.24 (d, 1H), 8.48 (s, 1H), 8.56 (s,1H), 8.68 (s, 2H), 9.04 (s, 1H), 9.56 (s, 1H).

Example 15-2422-[({2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}carbamoyl)amino]-N-methylbenzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 0.80 minutes);

MASS (ESI, Pos.): 526 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.46 (s, 3H), 6.04 (brs, 2H), 7.19-7.33 (m, 3H),7.47-7.65 (m, 4H), 7.72-7.80 (m, 2H), 7.98 (d, 1H), 8.12 (d, 1H),8.71-8.79 (m, 3H), 10.06 (s, 1H).

Example 15-2432-[({2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}carbamoyl)amino]-N-propyl-4-(trifluoromethyl)benzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 622 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 0.77 (t, 3H), 1.32-1.47 (m, 2H), 2.77-2.88 (m, 2H),6.15 (brs, 2H), 7.27-7.35 (m, 2H), 7.50-7.62 (m, 4H), 7.96-8.04 (m, 2H),8.17-8.25 (m, 1H), 8.54 (s, 1H), 8.76 (s, 2H), 8.89 (s, 1H), 10.22 (s,1H).

Example 15-2442-[({2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}carbamoyl)amino]-N,N-dimethylbenzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 0.85 minutes);

MASS (ESI, Pos.): 540 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.69 (s, 6H), 5.86 (s, 2H), 7.25-7.32 (m, 3H), 7.43(d, 1H), 7.49-7.56 (m, 2H), 7.62-7.78 (m, 2H), 7.96 (d, 1H), 8.14 (d,1H), 8.74 (s, 2H), 8.80 (s, 1H), 10.14 (s, 1H).

Example 15-2452-[({2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}carbamoyl)amino]-N-(2-hydroxypropyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 0.97 minutes);

MASS (ESI, Pos.): 652 (M+H)⁺.

Example 15-2462-{[(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)carbamoyl]amino}-N-ethyl-N-methyl-4-(trifluoromethyl)benzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 1.07 minutes);

MASS (ESI, Pos.): 656 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.04 (s, 3H), 2.80 (s, 3H), 3.20 (q, 2H), 6.49 (s,2H), 7.25-7.32 (m, 2H), 7.50-7.64 (m, 4H), 7.97 (d, 1H), 8.26-8.29 (m,1H), 8.55 (d, 1H), 8.75 (s, 2H), 8.93 (s, 1H), 10.31 (s, 1H).

Example 15-2472-{[(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)carbamoyl]amino}-N,N-diethyl-4-(trifluoromethyl)benzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 1.09 minutes);

MASS (ESI, Pos.): 670 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.03 (s, 6H), 3.27-3.35 (m, 4H), 6.48 (s, 2H),7.25-7.32 (m, 2H), 7.50-7.61 (m, 4H), 8.00 (d, 1H), 8.27-8.30 (m, 1H),8.47-8.49 (m, 1H), 8.75 (s, 2H), 8.85 (s, 1H), 10.30 (s, 1H).

Example 15-2481-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(1-azetidinylsulfonyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.05 minutes);

MASS (ESI, Pos.): 654 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.02-2.15 (m, 2H), 3.77-3.82 (m, 4H), 6.49 (s, 2H),7.25-7.32 (m, 2H), 7.49-7.66 (m, 4H), 7.99 (d, 1H), 8.26-8.29 (m, 1H),8.68 (d, 1H), 8.75 (s, 2H), 8.94 (s, 1H), 10.35 (s, 1H).

Example 15-2492-{[(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)carbamoyl]amino}-N-(2-hydroxypropyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide

LC-MS/ELSD: Retention Time: 1.02 minutes;

MASS (ESI, Pos.): 686 (M+H).

Example 15-2501-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.95 minutes);

MASS (ESI, Pos.): 587 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.17 (s, 6H), 1.61-1.70 (m, 2H), 2.63-2.75 (m, 2H),4.37 (s, 1H), 5.86 (s, 2H), 7.27 (d, 2H), 7.32-7.44 (m, 3H), 7.51 (d,2H), 7.95 (d, 1H), 8.09 (s, 1H), 8.39 (s, 1H), 8.74 (s, 2H), 9.28 (s,1H).

Example 15-2511-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(3-hydroxy-3-methyl-1-butyn-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 583 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.54 (s, 6H), 5.60 (s, 1H), 5.86 (s, 2H), 7.28 (d,2H), 7.35 (dd, 1H), 7.43 (d, 1H), 7.52 (d, 2H), 7.58 (d, 1H), 7.96 (d,1H), 8.32 (s, 1H), 8.35 (d, 1H), 8.74 (s, 2H), 9.84 (s, 1H).

Example 16

The similar procedures as Example 6→Example 7 were carried out with4-amino-5-bromopyrimidine in place of 3-bromo-5-chloropyridin-2-amine,and a corresponding carbamate or isocyanate compound in place of thecompound produced in Example 3 to give the present compounds having thefollowing physical characteristics.

Example 16-11-(2-(4-(4-aminopyrimidin-5-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.58 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 6.66 (s, 2H), 7.29 (d, 2H), 7.40 (d, 1H), 7.48 (d,2H), 7.75 (d, 1H), 8.03 (s, 1H), 8.36 (s, 1H), 8.57 (s, 1H), 8.75-8.79(m, 3H), 9.72 (s, 1H).

Example 16-21-(2-(4-(4-aminopyrimidin-5-yl)phenoxy)pyrimidin-5-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.51 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 6.67 (s, 2H), 7.28 (d, 2H), 7.43-7.54 (m, 4H), 8.03(s, 1H), 8.36 (s, 1H), 8.52 (d, 1H), 8.75 (s, 2H), 9.10 (s, 1H), 9.30(s, 1H).

Example 16-31-(2-(4-(4-aminopyrimidin-5-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.45 (Ethyl Acetate:Methanol:Aqueous Ammonia=9:1:0.5);

¹H-NMR (DMSO-d₆): δ 6.66 (s, 2H), 7.26 (d, 2H), 7.45-7.58 (m, 5H), 7.89(d, 1H), 8.03 (s, 1H), 8.24 (s, 1H), 8.35 (s, 1H), 8.38 (s, 1H),8.60-8.68 (m, 4H), 9.24 (s, 1H).

Example 16-41-(2-(4-(4-aminopyrimidin-5-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.51 (Ethyl Acetate:Methanol:Aqueous Ammonia=9:1:0.5);

¹H-NMR (DMSO-d₆): δ 6.67 (s, 2H), 7.27-7.34 (m, 3H), 7.47-7.54 (m, 3H),7.62 (d, 1H), 7.97 (s, 1H), 8.03 (s, 1H), 8.36 (s, 1H), 8.75 (s, 2H),8.99 (s, 1H), 9.32 (s, 1H).

Example 16-51-(2-(4-(4-aminopyrimidin-5-yl)phenoxy)pyrimidin-5-yl)-3-(2-phenyl-5-(trifluoromethyl)pyridin-3-yl)urea

TLC:Rf 0.25 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 6.65 (s, 2H), 7.26 (d, 2H), 7.45-7.67 (m, 7H), 8.02(s, 1H), 8.35 (s, 1H), 8.55 (s, 1H), 8.67 (s, 2H), 8.72 (s, 1H), 8.74(s, 1H), 9.60 (s, 1H).

Example 16-61-(2-(4-(4-aminopyrimidin-5-yl)phenoxy)pyrimidin-5-yl)-3-(2-(3,4-dimethylphenyl)-5-(trifluoromethyl)pyridin-3-yl)urea

TLC:Rf 0.68 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 2.31 (s, 6H), 6.65 (s, 2H), 7.25-7.48 (m, 7H), 8.02(s, 1H), 8.35-8.40 (m, 2H), 8.60-8.65 (m, 3H), 8.77 (s, 1H), 9.55 (s,1H).

Example 16-71-(2-(4-(4-aminopyrimidin-5-yl)phenoxy)pyrimidin-5-yl)-3-(3-(tert-butyl)-1-(2,3-dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl)urea

TLC:Rf 0.49 (Ethyl Acetate:Methanol=10:1);

¹H-NMR (DMSO-d₆): δ 1.25 (s, 9H), 2.05 (quint., 2H), 2.85-2.95 (m, 4H),6.33 (s, 1H), 6.65 (s, 2H), 7.18-7.30 (m, 3H), 7.30-7.36 (m, 2H), 7.46(d, 2H), 8.02 (s, 1H), 8.35 (s, 1H), 8.56 (s, 1H), 8.66 (s, 2H), 9.19(s, 1H).

Example 16-81-(2-(4-(4-aminopyrimidin-5-yl)phenoxy)pyrimidin-5-yl)-3-(3-(tert-butyl)-1-(o-tolyl)-1H-pyrazol-5-yl)urea

TLC:Rf 0.48 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.25 (s, 9H), 1.99 (s, 3H), 6.34 (s, 1H), 6.66 (s,2H), 7.25 (d, 2H), 7.31-7.48 (m, 6H), 8.02 (s, 1H), 8.35 (s, 1H), 8.40(s, 1H), 8.64 (s, 2H), 9.07 (s, 1H)

Example 17 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine

A solution of 5-chloropyrazolo[1,5-a]pyrimidine (9 g) in THF (147 mL)was stirred at 5° C. The reaction mixture was added withN-bromosuccinimide (11 g) and stirred at room temperature for 1 hour.The reaction mixture was added with a sodium hydrogen sulfite aqueoussolution and stirred for 5 minutes followed by distillation of THF underreduced pressure. The obtained residue was added with a saturated sodiumcarbonate aqueous solution and extracted with ethyl acetate. Theobtained organic layer was washed twice with a saturated sodiumcarbonate aqueous solution, once with water and once with a saturatedsodium chloride aqueous solution. The obtained organic layer was driedover sodium sulfate and filtered followed by distillation of the solventto give the titled compound having the following physicalcharacteristics (13.6 g).

TLC:Rf 0.40 (Hexane:Ethyl Acetate=4:1);

¹H-NMR (DMSO-d₆): δ 6.85 (d, 1H), 8.12 (s, 1H), 8.54 (d, 1H).

Example 18 3-bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine

To a solution of the compound produced in Example 17 (2.5 g) indimethylsulfoxide (hereinafter abbreviated as DMSO) (20 mL) were addedtriethylamine (2.25 mL) and pyrrolidine (1.3 mL) and the mixture wasstirred at room temperature for 1 hour. The reaction mixture was pouredto a sodium hydrogen carbonate aqueous solution and extracted with ethylacetate. The obtained organic layer was washed with water and asaturated sodium chloride aqueous solution and dried over anhydroussodium sulfate. The obtained organic layer was filtered followed bydistillation of the solvent. The obtained residue was added withtert-butyl methyl ether and filtered to give the titled compound havingthe following physical characteristics (2.49 g).

TLC:Rf 0.30 (Hexane:Ethyl Acetate=2:1);

¹H-NMR (DMSO-d₆): δ 1.95-2.12 (br s, 4H), 3.35-3.85 (br s, 4H), 6.14 (d,1H), 7.80 (s, 1H), 8.18 (d, 1H).

Example 192-(4-(5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-amine

The similar procedure as Example 6 was carried out with the compoundproduced in Example 18 in place of 3-bromo-5-chloropyridin-2-amine togive the titled compound having the following physical characteristics.

TLC:Rf 0.52 (Dichloromethane:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 1.94-2.08 (br s, 4H), 3.40-3.74 (br s, 4H),5.05-5.35 (br s, 2H), 6.41 (d, 1H), 7.04 (d, 2H), 7.96 (s, 2H), 8.05 (d,2H), 8.33 (s, 1H), 8.61 (d, 1H).

Example 201-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

The similar procedure as Example 7 was carried out with the compoundproduced in Example 19 in place of the compound produced in Example 6 togive the present compound having the following physical characteristics.

TLC:Rf 0.50 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 1.94-2.08 (br s, 4H), 3.40-3.72 (br s, 4H), 6.42 (d,1H), 6.67 (dd, 1H), 7.15 (d, 2H), 7.51 (dd, 1H), 7.74 (d, 1H), 7.95 (d,1H), 8.10 (d, 2H), 8.36 (s, 1H), 8.40 (d, 1H), 8.58 (d, 1H), 8.62 (d,1H), 8.67 (s, 2H), 9.68 (br s, 1H), 9.92 (br s, 1H).

Example 21

The similar procedure as Example 7 was carried out with the compoundproduced in Example 19 or a corresponding amine compound in place of thecompound produced in Example 19, and the compound produced in Example 3or a corresponding carbamate or isocyanate compound in place of thecompound produced in Example 3 to give the present compounds having thefollowing physical characteristics.

Example 21-11-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.22 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.12-4.18 (m, 4H), 6.23 (d, 1H),7.10-7.16 (m, 2H), 7.46-7.58 (m, 3H), 7.86-7.90 (m, 1H), 8.03-8.09 (m,2H), 8.22 (s, 1H), 8.35-8.39 (m, 2H), 8.60-8.68 (m, 5H), 9.21 (s, 1H).

Example 21-21-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.33 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.37 (t, 2H), 3.65 (s, 3H), 4.15 (t, 4H), 6.23 (d,1H), 6.44 (d, 1H), 7.14 (d, 2H), 7.48 (d, 2H), 7.61 (d, 1H), 8.04-8.10(m, 3H), 8.36 (s, 1H), 8.55 (s, 1H), 8.62 (d, 1H), 8.64 (s, 2H), 9.46(s, 1H).

Example 21-31-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.66 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.35-2.44 (m, 5H), 4.15 (t, 4H), 6.24 (d, 1H), 6.44(d, 1H), 7.14 (d, 2H), 7.48 (dd, 1H), 7.69 (d, 1H), 8.06 (d, 2H), 8.26(d, 1H), 8.36 (s, 1H), 8.56 (d, 1H), 8.62 (d, 1H), 8.67 (s, 2H), 9.78(s, 1H), 9.87 (s, 1H).

Example 21-41-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.47 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.37 (t, 2H), 4.15 (t, 4H), 6.24 (d, 1H), 6.68 (d,1H), 7.14 (d, 2H), 7.51 (dd, 1H), 7.74 (d, 1H), 7.95 (d, 1H), 8.07 (d,2H), 8.36 (s, 1H), 8.40 (d, 1H), 8.58-8.67 (m, 4H), 9.68 (s, 1H), 9.92(s, 1H).

Example 21-51-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.19 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.33-2.43 (m, 2H), 4.06-4.12 (m, 4H), 6.25 (d, 1H),7.13-7.20 (m, 2H), 7.33 (d, 1H), 7.52 (t, 1H), 7.62 (d, 1H), 7.98 (s,1H), 8.05-8.12 (m, 2H), 8.39 (s, 1H), 8.65 (d, 1H), 8.71 (s, 2H), 8.96(s, 1H), 9.31 (s, 1H).

Example 21-61-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.34 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 1.94-2.05 (m, 4H), 3.51-3.67 (m, 4H), 6.43 (d, 1H),7.14 (d, 2H), 7.47-7.58 (m, 3H), 7.89 (dd, 1H), 8.10 (d, 2H), 8.23 (s,1H), 8.38 (d, 2H), 8.61-8.68 (m, 5H), 9.22 (s, 1H).

Example 21-71-(2-(4-(5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.68 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 1.95-2.04 (m, 4H), 3.52-3.65 (m, 4H), 6.44 (d, 1H),7.24 (d, 2H), 7.46 (d, 1H), 7.57 (t, 2H), 7.72 (d, 1H), 7.93 (s, 1H),8.16 (d, 2H), 8.36 (s, 1H), 8.64 (d, 1H), 8.76 (s, 2H), 10.23 (s, 1H).

Example 21-81-(2-phenyl-5-(trifluoromethyl)pyridin-3-yl)-3-(2-(4-(5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.76 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 1.92-2.05 (m, 4H), 3.52-3.65 (m, 4H), 6.43 (d, 1H),7.15 (d, 2H), 7.56 (d, 3H), 7.65-7.68 (m, 2H), 8.11 (d, 2H), 8.39 (s,1H), 8.41 (s, 1H), 8.62 (d, 1H), 8.65 (s, 2H), 8.72 (s, 1H), 8.76 (s,1H), 9.44 (s, 1H).

Example 21-91-(2-(4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.45 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 7.21 (d, 2H), 7.46-7.58(m, 3H), 7.89 (dt, 1H), 8.10 (d, 2H), 8.23 (s, 1H), 8.39 (s, 1H), 8.58(s, 1H), 8.64-8.68 (m, 4H), 8.93 (d, 1H), 9.23 (s, 1H).

Example 21-101-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.45 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 4.04 (s, 3H), 6.62 (d, 1H), 6.68 (t, 1H), 7.20-7.26(m, 2H), 7.53 (dd, 1H), 7.76 (d, 1H), 7.96 (d, 1H), 8.09-8.14 (m, 2H),8.42 (d, 1H), 8.58-8.61 (m, 2H), 8.70 (s, 2H), 8.94 (d, 1H), 9.71 (s,1H), 9.96 (s, 1H).

Example 21-111-(2-(4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.45 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 4.04 (s, 3H), 6.62 (d, 1H), 7.21-7.27 (m, 2H), 7.33(d, 1H), 7.52 (t, 1H), 7.63 (d, 1H), 7.96-8.00 (m, 1H), 8.10-8.15 (m,2H), 8.59 (s, 1H), 8.72 (s, 2H), 8.94 (d, 1H), 8.99 (s, 1H), 9.32 (s,1H).

Example 21-121-(2-(4-(5-((2-hydroxy-2-methylpropyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.41 (Chloroform:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.19 (s, 6H), 3.43 (d, 2H), 4.62 (s, 1H), 6.48 (d,1H), 7.14-7.20 (m, 2H), 7.33 (d, 1H), 7.48-7.56 (m, 2H), 7.63 (d, 1H),7.96-8.00 (m, 1H), 8.06-8.12 (m, 2H), 8.31 (s, 1H), 8.47 (d, 1H), 8.71(s, 2H), 8.97 (s, 1H), 9.32 (s, 1H).

Example 21-131-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.22 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.11 (dd, 1H), 7.24 (d, 2H), 7.47-7.58 (m, 3H),7.86-7.91 (m, 1H), 8.16 (d, 2H), 8.22 (s, 1H), 8.39 (s, 1H), 8.60-8.68(m, 5H), 8.76 (s, 1H), 9.16 (dd, 1H), 9.23 (s, 1H).

Example 21-141-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.65 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.11 (dd, 1H), 7.25 (d, 2H), 7.32 (d, 1H), 7.51 (t,1H), 7.61 (d, 1H), 7.97 (s, 1H), 8.17 (d, 2H), 8.66 (dd, 1H), 8.71 (s,2H), 8.76 (s, 1H), 8.98 (s, 1H), 9.16 (dd, 1H), 9.32 (s, 1H).

Example 21-151-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.74 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 6.67 (t, 1H), 7.11 (dd, 1H), 7.25 (d, 2H), 7.52 (dd,1H), 7.74 (d, 1H), 7.95 (d, 1H), 8.17 (d, 2H), 8.40 (d, 1H), 8.58 (d,1H), 8.64-8.70 (m, 3H), 8.75 (s, 1H), 9.15 (dd, 1H), 9.67 (s, 1H), 9.94(s, 1H).

Example 21-161-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.60 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.10 (dd, 1H), 7.24 (d, 2H), 7.61 (d, 1H), 7.73 (d,1H), 8.09 (s, 1H), 8.16 (d, 2H), 8.57 (s, 1H), 8.66 (s, 2H), 8.67-8.70(m, 2H), 8.75 (s, 2H), 9.15 (s, 1H), 9.63 (s, 1H).

Example 21-171-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.65 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.11 (dd, 1H), 7.26 (d, 2H), 7.37-7.44 (m, 1H), 7.46(t, 1H), 8.17 (d, 2H), 8.51 (dd, 1H), 8.65 (dd, 1H), 8.72 (s, 2H), 8.75(s, 1H), 9.08 (s, 1H), 9.15 (dd, 1H), 9.28 (s, 1H).

Example 21-181-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.69 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.10 (dd, 1H), 7.26 (d, 2H), 7.40 (dd, 1H), 7.72 (d,1H), 8.17 (d, 2H), 8.56 (d, 1H), 8.66 (dd, 1H), 8.73 (s, 2H), 8.75 (s,1H), 8.77 (s, 1H), 9.15 (dd, 1H), 9.69 (s, 1H).

Example 21-191-(2-methyl-5-(trifluoromethyl)phenyl)-3-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.72 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.32 (s, 3H), 7.11 (dd, 1H), 7.26 (d, 2H), 7.29 (d,1H), 7.42 (d, 1H), 8.17 (d, 2H), 8.27 (s, 1H), 8.37 (s, 1H), 8.66 (dd,1H), 8.73 (s, 2H), 8.76 (s, 1H), 9.16 (dd, 1H), 9.31 (s, 1H).

Example 21-201-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.76 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.11 (dd, 1H), 7.20-7.30 (m, 3H), 7.54-7.72 (m, 2H),8.18 (d, 2H), 8.65-8.76 (m, 4H), 9.09 (s, 1H), 9.16-9.20 (m, 1H), 9.51(s, 1H).

Example 21-211-(4-methyl-3-(trifluoromethyl)phenyl)-3-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.76 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.36 (s, 3H), 7.10 (dd, 1H), 7.25 (d, 2H), 7.33 (d,1H), 7.52 (dd, 1H), 7.88 (d, 1H), 8.17 (d, 2H), 8.65 (dd, 1H), 8.70 (s,2H), 8.75 (s, 1H), 8.91 (s, 1H), 9.15 (d, 1H), 9.17 (d, 1H).

Example 21-221-(2-phenyl-5-(trifluoromethyl)pyridin-3-yl)-3-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.77 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.11 (dd, 1H), 7.25 (d, 2H), 7.52-7.62 (m, 3H),7.62-7.69 (m, 2H), 8.17 (d, 2H), 8.41 (s, 1H), 8.62-8.80 (m, 6H), 9.16(dd, 1H), 9.45 (d, 1H).

Example 21-231-(3-(difluoromethyl)phenyl)-3-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.73 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.00 (t, 1H), 7.11 (dd, 1H), 7.18 (d, 1H), 7.26 (d,2H), 7.42 (t, 1H), 7.52 (d, 1H), 7.77 (s, 1H), 8.17 (d, 2H), 8.66 (dd,1H), 8.71-8.76 (m, 3H), 8.89 (s, 1H), 9.17 (d, 2H).

Example 21-241-(3,5-difluorophenyl)-3-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.74 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 6.80 (dt, 1H), 7.11 (dd, 1H), 7.19 (dd, 2H), 7.26(d, 2H), 8.17 (d, 2H), 8.66 (dd, 1H), 8.70 (s, 2H), 8.75 (s, 1H), 9.00(s, 1H), 9.16 (dd, 1H), 9.30 (s, 1H).

Example 21-251-(2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl)-3-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.63 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.45-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H), 6.65(t, 1H), 7.15 (d, 2H), 7.74 (dd, 1H), 7.82 (d, 1H), 7.93 (d, 1H), 8.60(d, 2H), 8.36 (s, 1H), 8.43 (dd, 2H), 8.63 (d, 1H), 8.67 (s, 2H), 9.54(s, 1H), 9.26 (s, 1H).

Example 21-261-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.44 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 2.36-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H), 7.16(d, 2H), 7.68 (dd, 1H), 7.87 (s, 1H), 8.07 (d, 2H), 8.37 (s, 1H), 8.42(d, 1H), 8.63 (d, 1H), 8.72 (s, 2H), 8.78 (s, 1H), 9.73 (s, 1H).

Example 21-271-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-phenylurea

TLC:Rf 0.20 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.33-2.43 (m, 2H), 4.11-4.19 (m, 4H), 6.25 (d, 1H),6.95-7.02 (m, 1H), 7.13-7.19 (m, 2H), 7.25-7.34 (m, 2H), 7.42-7.47 (m,2H), 8.06-8.10 (m, 2H), 8.38 (s, 1H), 8.64 (d, 1H), 8.70 (s, 2H), 8.82(s, 1H), 8.91 (s, 1H).

Example 21-281-(2-chloro-4-(trifluoromethyl)phenyl)-3-(2-(4-(5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.62 (Dichloromethane:Ethyl Acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 1.92-2.06 (br s, 4H), 3.40-3.70 (br s, 4H), 6.43 (d,1H), 7.17 (d, 2H), 7.69 (dd, 1H), 7.88 (d, 1H), 8.12 (d, 2H), 8.37 (s,1H), 8.43 (d, 1H), 8.63 (d, 1H), 8.72 (s, 2H), 8.79 (s, 1H), 9.75 (s,1H).

Example 21-291-(2-chloro-4-(trifluoromethyl)phenyl)-3-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.80 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.10 (dd, 1H), 7.26 (d, 2H), 7.68 (dd, 1H), 7.87 (s,1H), 8.17 (d, 2H), 8.42 (d, 1H), 8.66 (dd, 1H), 8.73 (s, 2H), 8.75 (s,1H), 8.78 (s, 1H), 9.16 (d, 1H), 9.74 (s, 1H).

Example 21-301-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 602 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.65 (s, 3H), 4.03 (s, 3H), 6.45 (d, 1H), 6.61 (d,1H), 7.22 (d, 2H), 7.46-7.52 (m, 2H), 7.62 (d, 1H), 8.09-8.12 (m, 3H),8.56 (s, 1H), 8.59 (s, 1H), 8.66 (s, 2H), 8.93 (d, 1H), 9.48 (s, 1H).

Example 21-311-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

¹H-NMR (DMSO-d₆): δ 2.37 (s, 3H), 4.03 (s, 3H), 6.45 (d, 1H), 6.61 (d,1H), 7.20-7.25 (m, 2H), 7.48 (dd, 1H), 7.69 (d, 1H), 8.09-8.13 (m, 2H),8.28 (d, 1H), 8.57 (d, 1H), 8.58 (s, 1H), 8.68 (s, 2H), 8.93 (d, 1H),9.80 (s, 1H), 9.90 (s, 1H).

Example 21-321-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.08 minutes);

MASS (ESI, Pos.): 602 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.14 (s, 3H), 4.03 (s, 3H), 6.61 (d, 1H), 7.22 (d,2H), 7.49 (dd, 1H), 7.70 (d, 1H), 7.78 (s, 1H), 8.11 (d, 2H), 8.18 (s,1H), 8.57-8.58 (m, 2H), 8.69 (s, 2H), 8.93 (d, 1H), 9.83 (s, 1H), 9.95(s, 1H).

Example 21-331-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-pyridinyl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.92 minutes);

MASS (ESI, Pos.): 599 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 7.19-7.24 (m, 2H),7.53-7.57 (m, 2H), 7.75 (dd, 1H), 7.88-7.92 (m, 1H), 8.08-8.12 (m, 2H),8.24-8.29 (m, 2H), 8.58 (s, 1H), 8.64-8.68 (m, 4H), 8.93 (d, 1H), 9.28(brs, 1H).

Example 21-341-[2-chloro-5-(trifluoromethyl)phenyl]-3-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.05 minutes);

MASS (ESI, Pos.): 556 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 7.24 (d, 2H), 7.40 (dd,1H), 7.73 (d, 1H), 8.11 (d, 2H), 8.57-8.59 (d, 2H), 8.73 (s, 2H), 8.78(s, 1H), 8.94 (d, 1H), 9.70 (s, 1H).

Example 21-351-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-methyl-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.00 minute);

MASS (ESI, Pos.): 536 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32 (s, 3H), 4.03 (s, 3H), 6.61 (d, 1H), 7.24 (d,2H), 7.30 (d, 1H), 7.41 (d, 1H), 8.09-8.13 (m, 2H), 8.28 (s, 1H), 8.37(s, 1H), 8.59 (s, 1H), 8.73 (s, 2H), 8.94 (d, 1H), 9.32 (s, 1H).

Example 21-361-(2,4-dichlorophenyl)-3-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.03 minutes);

MASS (ESI, Pos.): 522 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 7.23 (d, 2H), 7.39 (dd,1H), 7.63 (d, 1H), 8.10-8.16 (m, 3H), 8.57 (s, 1H), 8.59 (s, 1H), 8.71(s, 2H), 8.93 (d, 1H), 9.58 (s, 1H).

Example 21-371-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.32 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.62 (d, 1H), 7.12-7.17 (m, 2H),7.46-7.57 (m, 3H), 7.86-7.90 (m, 1H), 8.06-8.11 (m, 2H), 8.22 (s, 1H),8.37-8.38 (m, 2H), 8.61-8.68 (m, 5H), 9.21 (s, 1H).

Example 21-381-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.30 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.63 (d, 1H), 6.67-6.68 (m, 1H),7.14-7.17 (m, 2H), 7.52 (dd, 1H), 7.75 (d, 1H), 7.95 (d, 1H), 8.08-8.11(m, 2H), 8.39 (s, 1H), 8.41 (d, 1H), 8.59 (d, 1H), 8.64 (d, 1H), 8.68(s, 2H), 9.69 (s, 1H), 9.93 (s, 1H).

Example 21-391-[2-fluoro-5-(trifluoromethyl)phenyl]-3-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 540 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 7.21-7.26 (m, 2H),7.39-7.53 (m, 2H), 8.09-8.14 (m, 2H), 8.53 (dd, 1H), 8.59 (s, 1H), 8.73(s, 2H), 8.93 (d, 1H), 9.02-9.36 (br s, 2H).

Example 21-401-[5-chloro-2-(3-pyridinyl)phenyl]-3-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 565 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.60 (d, 1H), 7.20-7.30 (m, 4H), 7.53(dd, 1H), 7.81-7.85 (m, 1H), 8.08-8.12 (m, 4H), 8.55-8.64 (m, 5H), 8.93(d, 1H), 9.18 (s, 1H).

Example 21-411-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.09 minutes);

MASS (ESI, Pos.): 656 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 7.12 (d, 1H), 7.20-7.24(m, 2H), 7.58 (dd, 1H), 7.10 (d, 1H), 8.09-8.13 (m, 2H), 8.47-8.48 (m,2H), 8.58 (s, 2H), 8.65 (s, 2H), 8.93 (d, 1H), 9.46 (s, 1H).

Example 21-421-{2-[4-(5-ethoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.98 minutes);

MASS (ESI, Pos.): 613 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.40 (t, 3H), 4.49 (q, 2H), 6.58 (d, 1H), 7.18-7.22(m, 2H), 7.47-7.58 (m, 3H), 7.87-7.91 (m, 1H), 8.05-8.10 (m, 2H), 8.23(s, 1H), 8.39 (s, 1H), 8.57 (s, 1H), 8.64-8.68 (m, 4H), 8.92 (d, 1H),9.23 (s, 1H).

Example 21-431-{2-[4-(5-cyclobutylpyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 1.03 minutes);

MASS (ESI, Pos.): 623 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.85-2.12 (m, 2H), 2.33-2.42 (m, 4H), 3.73-3.84 (m,1H), 6.97 (d, 1H), 7.24 (d, 2H), 7.47-7.58 (m, 3H), 7.87-7.91 (m, 1H),8.18-8.23 (m, 3H), 8.39 (s, 1H), 8.64-8.68 (m, 5H), 9.01 (d, 1H), 9.23(s, 1H).

Example 21-441-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.09 minutes);

MASS (ESI, Pos.): 589 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.62 (d, 1H), 7.23 (d, 2H), 7.58 (dd,1H), 8.05-8.13 (m, 3H), 8.33 (s, 2H), 8.59 (s, 1H), 8.65 (d, 1H), 8.70(s, 2H), 8.93 (d, 1H), 9.66 (s, 1H), 10.00 (s, 1H).

Example 21-451-[5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl]-3-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 99% (Retention Time: 1.08 minutes);

MASS (ESI, Pos.): 555 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 7.20-7.25 (m, 2H), 7.29(dd, 1H), 7.80 (d, 1H), 8.09-8.13 (m, 2H), 8.26 (s, 2H), 8.33 (d, 1H),8.58 (s, 1H), 8.69 (s, 2H), 8.93 (d, 1H), 9.36 (s, 1H), 9.91 (s, 1H).

Example 21-461-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.24 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.31-2.44 (m, 2H), 4.10-4.19 (m, 4H), 6.24 (d, 1H),7.10-7.18 (m, 2H), 7.39-7.59 (d, 7H), 8.03-8.12 (m, 3H), 8.37 (s, 1H),8.41 (s, 1H), 8.60-8.66 (m, 3H), 9.37 (s, 1H).

Example 21-471-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(6-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.33 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.32-2.43 (m, 2H), 2.55 (s, 3H), 4.10-4.19 (m, 4H),6.24 (d, 1H), 7.11-7.18 (m, 2H), 7.40-7.51 (m, 3H), 7.76 (dd, 1H),8.03-8.10 (m, 2H), 8.18 (s, 1H), 8.37 (s, 1H), 8.41-8.43 (m, 1H), 8.51(d, 1H), 8.61-8.69 (m, 3H), 9.25 (s, 1H).

Example 21-481-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(6-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.30 (Methylene chloride:Ethyl acetate:Methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 2.55 (s, 3H), 3.19 (s, 6H), 6.63 (d, 1H), 7.15 (d,2H), 7.38-7.52 (m, 3H), 7.76 (dd, 1H), 8.10 (d, 2H), 8.18 (s, 1H), 8.38(s, 1H), 8.42 (s, 1H), 8.50 (d, 1H), 8.64 (s, 2H), 8.64 (d, 1H), 9.25(s, 1H).

Example 21-491-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[4′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.32 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.30-2.45 (m, 5H), 4.10-4.19 (m, 4H), 6.24 (d, 1H),7.11-7.18 (m, 2H), 7.30-7.47 (m, 6H), 8.01-8.10 (m, 3H), 8.37 (s, 1H),8.42-8.45 (m, 1H), 8.62-8.66 (m, 3H), 9.39 (s, 1H).

Example 21-501-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-phenyl-5-(trifluoromethyl)-3-pyridinyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 612 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.63 (d, 1H), 7.12-7.19 (m, 2H),7.51-7.68 (m, 5H), 8.05-8.13 (m, 2H), 8.36-8.47 (m, 2H), 8.62-8.67 (m,3H), 8.71-8.73 (m, 1H), 8.75-8.78 (m, 1H), 9.45 (s, 1H).

Example 21-511-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.98 minutes);

MASS (ESI, Pos.): 615 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 3.65 (s, 3H), 6.45 (d, 1H), 6.63 (d,1H), 7.13-7.19 (m, 2H), 7.44-7.54 (m, 2H), 7.62 (d, 1H), 8.06-8.14 (m,3H), 8.38 (s, 1H), 8.56 (s, 1H), 8.63-8.68 (m, 3H), 9.47 (s, 1H).

Example 21-521-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.04 minutes);

MASS (ESI, Pos.): 615 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.37 (s, 3H), 3.19 (s, 6H), 6.45 (d, 1H), 6.63 (d,1H), 7.14-7.21 (m, 2H), 7.48 (dd, 1H), 7.69 (d, 1H), 8.07-8.14 (m, 2H),8.28 (d, 1H), 8.39 (s, 1H), 8.57 (d, 1H), 8.63-8.70 (m, 3H), 9.80 (s,1H), 9.89 (s, 1H).

Example 21-531-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.07 minutes);

MASS (ESI, Pos.): 669 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.63 (d, 1H), 7.10-7.20 (m, 3H), 7.58(dd, 1H), 7.70 (d, 1H), 8.07-8.14 (m, 2H), 8.38 (s, 1H), 8.45-8.50 (m,2H), 8.57 (s, 1H), 8.63-8.67 (m, 3H), 9.45 (s, 1H).

Example 21-541-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]-3-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.06 minutes);

MASS (ESI, Pos.): 635 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.63 (d, 1H), 7.14-7.20 (m, 2H), 7.53(dd, 1H), 7.70 (d, 1H), 8.06-8.14 (m, 3H), 8.39 (s, 1H), 8.56-8.71 (m,5H), 9.09 (s, 1H), 9.78 (s, 1H).

Example 21-551-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.02 minutes);

MASS (ESI, Pos.): 670 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.63 (d, 1H), 7.13-7.20 (m, 2H),7.60-7.65 (m, 1H), 7.81 (d, 1H), 8.05-8.14 (m, 2H), 8.38 (s, 1H), 8.50(d, 1H), 8.57-8.68 (m, 4H), 9.21 (s, 1H), 9.33 (s, 1H).

Example 21-561-[5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl]-3-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.02 minutes);

MASS (ESI, Pos.): 568 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.63 (d, 1H), 7.13-7.21 (m, 2H), 7.29(dd, 1H), 7.80 (d, 1H), 8.07-8.14 (m, 2H), 8.26 (s, 2H), 8.32 (d, 1H),8.38 (s, 1H), 8.64 (d, 1H), 8.68 (s, 2H), 9.36 (s, 1H), 9.90 (s, 1H).

Example 21-571-[5-chloro-2-(3-pyridinyl)phenyl]-3-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.83 minutes);

MASS (ESI, Pos.): 578 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.62 (d, 1H), 7.15 (d, 2H), 7.21-7.30(m, 2H), 7.49-7.55 (m, 1H), 7.80-7.85 (m, 1H), 8.06-8.12 (m, 4H), 8.38(s, 1H), 8.56-8.66 (m, 5H), 9.17 (s, 1H).

Example 21-581-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.02 minutes);

MASS (ESI, Pos.): 601 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.60-6.68 (m, 2H), 7.16 (d, 2H), 7.74(dd, 1H), 7.80-7.85 (m, 1H), 7.92-7.95 (m, 1H), 8.10 (d, 2H), 8.37-8.46(m, 3H), 8.61-8.69 (m, 3H), 9.55 (s, 1H), 9.94 (s, 1H).

Example 21-591-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-fluoro-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.00 minute);

MASS (ESI, Pos.): 553 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.16 (s, 6H), 6.62 (d, 1H), 7.17 (d, 2H), 7.54 (d,1H), 7.70 (d, 1H), 8.06-8.16 (m, 2H), 8.32-8.42 (m, 2H), 8.64 (d, 1H),8.72 (s, 2H), 9.17 (s, 1H), 9.40 (s, 1H).

Example 21-601-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.97 minutes);

MASS (ESI, Pos.): 535 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.63 (d, 1H), 7.17 (d, 2H), 7.32 (d,1H), 7.51 (t, 1H), 7.62 (d, 1H), 7.97 (s, 1H), 8.10 (d, 2H), 8.39 (s,1H), 8.64 (d, 1H), 8.70 (s, 2H), 8.96 (s, 1H), 9.31 (s, 1H).

Example 21-611-[2-chloro-5-(trifluoromethyl)phenyl]-3-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.03 minutes);

MASS (ESI, Pos.): 569 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.63 (d, 1H), 7.17 (d, 2H), 7.39 (d,1H), 7.72 (d, 1H), 8.11 (d, 2H), 8.39 (s, 1H), 8.57 (d, 1H), 8.65 (d,1H), 8.72 (s, 2H), 8.78 (s, 1H), 9.69 (s, 1H).

Example 21-621-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-methyl-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.18 (Hexane:Ethyl acetate=1:4);

¹H-NMR (DMSO-d₆): δ 2.32 (s, 3H), 3.19 (s, 6H), 6.62 (d, 1H), 7.16 (d,2H), 7.29 (d, 1H), 7.41 (d, 1H), 8.10 (d, 2H), 8.27 (s, 1H), 8.37 (d,2H), 8.64 (d, 1H), 8.71 (s, 2H), 9.30 (s, 1H).

Example 21-631-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.99 minutes);

MASS (ESI, Pos.): 553 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.62 (d, 1H), 7.16 (d, 2H), 7.36-7.43(m, 1H), 7.45-7.54 (m, 1H), 8.10 (d, 2H), 8.38 (s, 1H), 8.49-8.56 (m,1H), 8.64 (d, 1H), 8.71 (s, 2H), 9.08 (s, 1H), 9.27 (s, 1H).

Example 21-641-(2,4-dichlorophenyl)-3-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 535 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.62 (d, 1H), 7.16 (d, 2H), 7.38 (dd,1H), 7.62 (d, 1H), 8.09 (d, 2H), 8.13 (d, 1H), 8.38 (s, 1H), 8.56 (s,1H), 8.64 (d, 1H), 8.70 (s, 2H), 9.56 (s, 1H).

Example 21-651-{2-[4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.43 (Methylene chloride:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 2.60 (s, 3H), 6.99 (d, 1H), 7.23 (d, 2H), 7.45-7.59(m, 3H), 7.89 (d, 1H), 8.14 (d, 2H), 8.23 (s, 1H), 8.39 (s, 1H),8.61-8.72 (m, 5H), 9.00 (d, 1H), 9.23 (s, 1H).

Example 21-661-(2-{4-[5-(ethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.31 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.22 (t, 3H), 3.38-3.47 (m, 2H), 6.26 (d, 1H),7.11-7.18 (m, 2H), 7.46-7.65 (m, 4H), 7.86-7.92 (m, 1H), 8.04-8.11 (m,2H), 8.23 (s, 1H), 8.31 (s, 1H), 8.37-8.41 (m, 1H), 8.46 (d, 1H),8.61-8.69 (m, 4H), 9.22 (s, 1H).

Example 21-671-(2-{4-[5-(ethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.36 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.22 (t, 3H), 2.38 (s, 3H), 3.36-3.48 (m, 2H), 6.26(d, 1H), 7.11-7.46 (m, 8H), 7.60 (t, 1H), 8.00-8.11 (m, 3H), 8.30 (s,1H), 8.42-8.48 (m, 2H), 8.63 (s, 2H), 9.39 (s, 1H).

Example 21-681-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.43 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.32-2.44 (m, 2H), 3.38 (s, 3H), 4.10-4.20 (m, 4H),6.24 (d, 1H), 7.13-7.20 (m, 2H), 7.61-7.66 (m, 1H), 8.04-8.11 (m, 3H),8.38 (s, 1H), 8.61-8.67 (m, 2H), 8.73 (s, 2H), 8.96 (s, 1H), 10.27 (s,1H).

Example 21-691-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.48 (Ethyl acetate);

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 3.38 (s, 3H), 6.63 (d, 1H), 7.15-7.22(m, 2H), 7.61-7.69 (m, 1H), 8.05-8.15 (m, 3H), 8.39 (s, 1H), 8.63-8.68(m, 2H), 8.73 (s, 2H), 8.96 (s, 1H), 10.27 (s, 1H).

Example 21-701-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.09 minutes);

MASS (ESI, Pos.): 611 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.62 (d, 1H), 7.15 (d, 2H), 7.40-7.58(m, 7H), 8.06-8.12 (m, 3H), 8.38 (s, 1H), 8.41 (s, 1H), 8.61-8.66 (m,3H), 9.36 (s, 1H).

Example 21-711-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[4′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.13 minutes);

MASS (ESI, Pos.): 625 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.39 (s, 3H), 3.19 (s, 6H), 6.62 (d, 1H), 7.15 (d,2H), 7.28-7.47 (m, 6H), 8.03 (s, 1H), 8.09 (d, 2H), 8.38 (s, 1H), 8.43(s, 1H), 8.61-8.66 (m, 3H), 9.39 (s, 1H).

Example 21-721-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[4′-ethyl-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.16 minutes);

MASS (ESI, Pos.): 639 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.24 (t, 3H), 2.68 (q, 2H), 3.19 (s, 6H), 6.62 (d,1H), 7.14 (d, 2H), 7.35-7.49 (m, 6H), 8.03-8.12 (m, 3H), 8.38 (s, 1H),8.41 (s, 1H), 8.61-8.66 (m, 3H), 9.38 (s, 1H).

Example 21-731-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.13 minutes);

MASS (ESI, Pos.): 625 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.38 (s, 3H), 3.19 (s, 6H), 6.62 (d, 1H), 7.14 (d,2H), 7.19-7.32 (m, 3H), 7.36-7.47 (m, 3H), 8.02 (s, 1H), 8.09 (s, 1H),8.11 (s, 1H), 8.38 (s, 1H), 8.44 (s, 1H), 8.64 (s, 2H), 8.66 (s, 1H),9.40 (s, 1H).

Example 21-741-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-ethyl-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.17 minutes);

MASS (ESI, Pos.): 639 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.22 (t, 3H), 2.68 (q, 2H), 3.19 (s, 6H), 6.62 (d,1H), 7.15 (d, 2H), 7.22-7.36 (m, 3H), 7.40-7.49 (m, 3H), 8.05 (s, 1H),8.10 (d, 2H), 8.38 (s, 1H), 8.40 (s, 1H), 8.63 (s, 2H), 8.66 (d, 1H),9.38 (s, 1H).

Example 21-751-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.14 minutes);

MASS (ESI, Pos.): 625 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.04 (s, 3H), 3.19 (s, 6H), 6.62 (d, 1H), 7.10-7.22(m, 3H), 7.26-7.46 (m, 5H), 7.70 (s, 1H), 8.09 (d, 2H), 8.38 (s, 1H),8.53 (s, 1H), 8.62 (s, 2H), 8.65 (s, 1H), 9.42 (s, 1H).

Example 21-761-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′,4′-dimethyl-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.17 minutes);

MASS (ESI, Pos.): 639 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.29 (s, 6H), 3.19 (s, 6H), 6.62 (d, 1H), 7.12-7.19(m, 3H), 7.19-7.22 (m, 1H), 7.30 (d, 1H), 7.36 (d, 1H), 7.42 (dd, 1H),8.00 (s, 1H), 8.09 (d, 2H), 8.38 (s, 1H), 8.44-8.48 (m, 1H), 8.62-8.67(m, 3H), 9.42 (s, 1H).

Example 21-771-(2-{4-[5-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.93 minutes);

MASS (ESI, Pos.): 599 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.93 (d, 3H), 3.41 (s, 3H), 6.27 (d, 1H), 7.17 (d,2H), 7.56-7.67 (m, 1H), 8.03-8.17 (m, 4H), 8.32 (s, 1H), 8.43-8.55 (m,2H), 8.73 (s, 2H), 9.03 (s, 1H), 10.33 (s, 1H).

Example 21-781-(2-{4-[5-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.38 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.04 (s, 3H), 2.92 (d, 3H), 6.28 (d, 1H), 7.11-7.45(m, 8H), 7.56-7.73 (m, 2H), 8.06-8.13 (m, 2H), 8.31 (s, 1H), 8.46 (d,1H), 8.51-8.54 (m, 1H), 8.62 (s, 2H), 9.42 (s, 1H).

Example 21-791-(2-{4-[5-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.30 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.92 (d, 3H), 6.27 (d, 1H), 7.11-7.18 (m, 2H),7.46-7.65 (m, 4H), 7.89 (dt, 1H), 8.06-8.14 (m, 2H), 8.23 (s, 1H), 8.31(s, 1H), 8.39 (s, 1H), 8.46 (d, 1H), 8.61-8.69 (m, 4H), 9.22 (s, 1H).

Example 21-801-(2-{4-[5-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[4-(trifluoromethyl)-2-biphenylyl]urea

TLC:Rf 0.42 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.92 (d, 3H), 6.26 (d, 1H), 7.11-7.17 (m, 2H),7.38-7.64 (m, 8H), 8.04-8.12 (m, 3H), 8.31 (s, 1H), 8.39-8.42 (m, 1H),8.46 (d, 1H), 8.63 (s, 2H), 9.35 (s, 1H).

Example 21-811-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfinyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.14 (Ethyl acetate);

¹H-NMR (DMSO-d₆): δ 2.89 (s, 3H), 3.19 (s, 6H), 6.62 (d, 1H), 7.15 (d,2H), 7.64 (d, 1H), 7.90 (d, 1H), 8.09 (d, 2H), 8.26 (s, 1H), 8.38 (s,1H), 8.63 (d, 1H), 8.70 (s, 2H), 9.22 (s, 1H), 9.65 (s, 1H).

Example 21-821-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-(1-hydroxyethyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 1.07 minutes);

MASS (ESI, Pos.): 655 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.36 (d, 3H), 3.19 (s, 6H), 4.74-4.83 (m, 1H),5.20-5.23 (m, 1H), 6.62 (d, 1H), 7.15 (d, 2H), 7.27-7.36 (m, 1H),7.38-7.56 (m, 5H), 8.04-8.26 (m, 3H), 8.37 (s, 1H), 8.38 (s, 1H), 8.63(s, 2H), 8.66 (s, 1H), 9.36 (s, 1H).

Example 21-831-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.05 minutes);

MASS (ESI, Pos.): 588 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 6.65-6.66 (m, 1H),7.20-7.25 (m, 2H), 7.73-7.83 (m, 2H), 7.93 (d, 1H), 8.00-8.13 (m, 2H),8.41-8.44 (m, 2H), 8.58 (s, 1H), 8.69 (s, 2H), 8.93 (d, 1H), 9.56 (brs,1H), 9.95 (brs, 1H).

Example 21-841-[3-(difluoromethyl)phenyl]-3-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.92 minutes);

MASS (ESI, Pos.): 504 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 7.00-7.24 (m, 4H), 7.42(t, 1H), 7.52 (d, 1H), 7.78 (s, 1H), 8.10-8.13 (m, 2H), 8.59 (s, 1H),8.71 (s, 2H), 8.90-8.95 (m, 2H), 9.16 (s, 1H).

Example 21-851-(2,5-dichlorophenyl)-3-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.04 minutes);

MASS (ESI, Pos.): 522 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 7.12 (dd, 1H), 7.21-7.26(m, 2H), 7.51 (d, 1H), 8.09-8.14 (m, 2H), 8.26 (s, 1H), 8.59 (s, 1H),8.63 (s, 1H), 8.72 (s, 2H), 8.93 (d, 1H), 9.66 (s, 1H).

Example 21-861-(2,5-difluorophenyl)-3-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.94 minutes);

MASS (ESI, Pos.): 490 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 6.81-6.89 (m, 1H),7.21-7.34 (m, 3H), 7.93-8.00 (m, 1H), 8.10-8.14 (m, 2H), 8.59 (s, 1H),8.72 (s, 2H), 8.92-8.96 (m, 2H), 9.25 (s, 1H).

Example 21-871-[2-chloro-4-(trifluoromethyl)phenyl]-3-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.06 minutes);

MASS (ESI, Pos.): 556 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 7.22-7.26 (m, 2H), 7.69(dd, 1H), 7.89 (d, 1H), 8.00-8.14 (m, 2H), 8.43 (d, 1H), 8.59 (s, 1H),8.73 (s, 2H), 8.79 (s, 1H), 8.93 (d, 1H), 9.76 (s, 1H).

Example 21-881-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.00 minute);

MASS (ESI, Pos.): 603 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.38 (s, 3H), 4.03 (s, 3H), 6.62 (d, 1H), 7.20-7.24(m, 2H), 7.58-7.71 (m, 2H), 8.08-8.13 (m, 2H), 8.33 (s, 1H), 8.51-8.60(m, 2H), 8.67 (s, 2H), 8.75 (s, 1H), 8.93 (d, 1H), 9.68 (s, 1H).

Example 21-891-[5-chloro-2-(1H-pyrazol-1-yl)phenyl]-3-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.05 minutes);

MASS (ESI, Pos.): 554 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.59-6.62 (m, 2H), 7.19-7.24 (m, 3H),7.51 (d, 1H), 7.89 (d, 1H), 8.08-8.12 (m, 2H), 8.26 (d, 1H), 8.27 (d,1H), 8.58 (s, 1H), 8.67 (s, 2H), 8.92 (d, 1H), 9.36 (s, 1H), 9.87 (s,1H).

Example 21-901-(2-{4-[5-(3-oxetanyloxy)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 94% (Retention Time: 0.89 minutes);

MASS (ESI, Pos.): 641 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.67-4.71 (m, 2H), 4.99 (t, 2H), 5.71-5.79 (m, 1H),6.69 (d, 1H), 7.21-7.26 (m, 2H), 7.47-7.58 (m, 3H), 7.83-7.91 (m, 1H),8.00-8.04 (m, 2H), 8.24 (s, 1H), 8.39 (s, 1H), 8.60 (s, 1H), 8.64-8.69(m, 4H), 9.00 (d, 1H), 9.24 (s, 1H).

Example 21-911-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-3-{2-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.95 minutes);

MASS (ESI, Pos.): 555 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.03 (s, 3H), 6.61 (d, 1H), 7.22 (d, 2H), 7.31 (dd,1H), 7.51 (d, 1H), 8.06-8.12 (m, 3H), 8.27 (d, 1H), 8.49 (s, 1H), 8.59(s, 1H), 8.65 (s, 2H), 8.70 (s, 1H), 8.93 (d, 1H), 9.58 (s, 1H).

Example 21-921-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 99% (Retention Time: 1.10 minutes);

MASS (ESI, Pos.): 681 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.23 (d, 1H),7.12-7.17 (m, 3H), 7.58 (dd, 1H), 7.70 (d, 1H), 8.04-8.09 (m, 2H), 8.37(s, 1H), 8.48 (s, 2H), 8.57 (s, 1H), 8.62-8.65 (m, 3H), 9.45 (s, 1H).

Example 21-931-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 98% (Retention Time: 1.10 minutes);

MASS (ESI, Pos.): 627 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.15 (s, 3H), 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24(d, 1H), 7.15 (d, 2H), 7.49 (dd, 1H), 7.70 (d, 1H), 7.78 (s, 1H),8.05-8.09 (m, 2H), 8.18 (s, 1H), 8.37 (s, 1H), 8.58 (d, 1H), 8.62-8.68(m, 3H), 9.82 (s, 1H), 9.94 (s, 1H).

Example 21-941-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(3-pyridinyl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 97% (Retention Time: 0.93 minutes);

MASS (ESI, Pos.): 624 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H),7.11-7.16 (m, 2H), 7.53-7.58 (m, 2H), 7.76 (dd, 1H), 7.88-7.92 (m, 1H),8.06 (d, 2H), 8.23 (s, 1H), 8.28 (d, 1H), 8.37 (s, 1H), 8.62-8.68 (m,5H), 9.27 (s, 1H).

Example 21-951-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[5-chloro-2-(H-pyrazol-1-yl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.03 minutes);

MASS (ESI, Pos.): 579 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H), 6.62(t, 1H), 7.13-7.17 (m, 2H), 7.22 (dd, 1H), 7.51 (d, 1H), 7.89 (d, 1H),8.04-8.09 (m, 2H), 8.26 (d, 1H), 8.28 (d, 1H), 8.37 (s, 1H), 8.62-8.66(m, 3H), 9.37 (s, 1H), 9.87 (s, 1H).

Example 21-961-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[5-chloro-2-(3-pyridinyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.86 minutes);

MASS (ESI, Pos.): 590 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H),7.11-7.16 (m, 2H), 7.23 (dd, 1H), 7.28 (d, 1H), 7.53 (dd, 1H), 7.80-7.85(m, 1H), 8.04-8.12 (m, 4H), 8.37 (s, 1H), 8.59-8.65 (m, 5H), 9.17 (s,1H).

Example 21-971-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.08 minutes);

MASS (ESI, Pos.): 614 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H),7.13-7.18 (m, 2H), 7.58 (dd, 1H), 8.05-8.09 (m, 3H), 8.32 (s, 2H), 8.38(s, 1H), 8.62-8.66 (m, 2H), 8.69 (s, 2H), 9.66 (s, 1H), 9.99 (s, 1H).

Example 21-981-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[5-chloro-2-(H-1,2,3-triazol-1-yl)phenyl]urea

Purity (LC-MS/ELSD): 96% (Retention Time: 0.94 minutes);

MASS (ESI, Pos.): 580 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H),7.12-7.17 (m, 2H), 7.31 (dd, 1H), 7.51 (d, 1H), 8.05-8.08 (m, 3H), 8.27(d, 1H), 8.37 (s, 1H), 8.48 (s, 1H), 8.59-8.65 (m, 4H), 9.57 (s, 1H).

Example 21-991-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.06 minutes);

MASS (ESI, Pos.): 580 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H),7.13-7.18 (m, 2H), 7.29 (dd, 1H), 7.80 (d, 1H), 8.05-8.09 (m, 2H), 8.26(s, 2H), 8.33 (d, 1H), 8.37 (s, 1H), 8.64 (d, 1H), 8.68 (s, 2H), 9.36(s, 1H), 9.90 (s, 1H).

Example 21-1001-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-chloro-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.03 minutes);

MASS (ESI, Pos.): 581 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H),7.14-7.19 (m, 2H), 7.40 (dd, 1H), 7.72 (d, 1H), 8.05-8.09 (m, 2H), 8.38(s, 1H), 8.57 (d, 1H), 8.64 (d, 1H), 8.72 (s, 2H), 8.78 (s, 1H), 9.69(s, 1H).

Example 21-1011-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.00 minute);

MASS (ESI, Pos.): 565 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H),7.13-7.18 (m, 2H), 7.38-7.53 (m, 2H), 8.04-8.09 (m, 2H), 8.37 (s, 1H),8.52 (dd, 1H), 8.63 (d, 1H), 8.71 (s, 2H), 9.08 (s, 1H), 9.27 (s, 1H).

Example 21-1021-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-methyl-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 1.03 minutes);

MASS (ESI, Pos.): 561 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 5H), 4.15 (t, 4H), 6.24 (d, 1H),7.14-7.18 (m, 2H), 7.29 (dd, 1H), 7.41 (d, 1H), 8.05-8.09 (m, 2H), 8.27(s, 1H), 8.37-8.38 (m, 2H), 8.64 (d, 1H), 8.72 (s, 2H), 9.31 (s, 1H).

Example 21-1031-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-(2,5-dichlorophenyl)urea

Purity (LC-MS/ELSD): 97% (Retention Time: 1.06 minutes);

MASS (ESI, Pos.): 547 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H),7.10-7.18 (m, 3H), 7.50 (d, 1H), 8.05-8.09 (m, 2H), 8.26 (d, 1H), 8.38(s, 1H), 8.63-8.71 (m, 4H), 9.66 (s, 1H).

Example 21-1041-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-(2,4-dichlorophenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.02 minutes);

MASS (ESI, Pos.): 547 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H),7.13-7.17 (m, 2H), 7.38 (dd, 1H), 7.63 (d, 1H), 8.04-8.09 (m, 2H), 8.14(d, 1H), 8.37 (s, 1H), 8.56 (brs, 1H), 8.66 (d, 1H), 8.70 (s, 2H), 9.57(brs, 1H).

Example 21-1051-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-(2,5-difluorophenyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.93 minutes);

MASS (ESI, Pos.): 515 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H),6.81-6.88 (m, 1H), 7.13-7.18 (m, 2H), 7.25-7.34 (m, 1H), 7.94-8.00 (m,1H), 8.05-8.09 (m, 2H), 8.38 (s, 1H), 8.64 (d, 1H), 8.70 (s, 2H), 8.95(s, 1H), 9.25 (s, 1H).

Example 21-1061-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3-(difluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 0.90 minutes);

MASS (ESI, Pos.): 529 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.15 (t, 4H), 6.24 (d, 1H),6.81-7.19 (m, 4H), 7.41 (t, 1H), 7.51 (d, 1H), 7.77 (s, 1H), 8.05-8.09(m, 2H), 8.38 (s, 1H), 8.64 (d, 1H), 8.70 (s, 2H), 8.89 (s, 1H), 9.16(s, 1H).

Example 21-1071-{6-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-3-pyridinyl}-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.96 minutes);

MASS (ESI, Pos.): 598 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.60 (d, 1H), 6.99 (d, 1H), 7.10-7.15(m, 2H), 7.45-7.58 (m, 3H), 7.87-7.91 (m, 1H), 7.97 (dd, 1H), 8.07-8.09(m, 4H), 8.42 (s, 1H), 8.56 (s, 1H), 8.64-8.69 (m, 2H), 8.92 (d, 1H),9.16 (s, 1H).

Example 21-1081-{6-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-3-pyridinyl}-3-[2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.08 minutes);

MASS (ESI, Pos.): 587 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.60 (d, 1H), 6.66-6.68 (m, 1H), 7.01(d, 1H), 7.11-7.16 (m, 2H), 7.49 (dd, 1H), 7.73 (d, 1H), 7.94 (d, 1H),7.99 (dd, 1H), 8.06-8.11 (m, 2H), 8.16 (d, 1H), 8.40 (d, 1H), 8.56 (s,1H), 8.60 (s, 1H), 8.92 (d, 1H), 9.54 (s, 1H), 9.80 (s, 1H).

Example 21-1091-{6-[4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-3-pyridinyl}-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.13 minutes);

MASS (ESI, Pos.): 655 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.60 (d, 1H), 7.01 (d, 1H), 7.12-7.15(m, 3H), 7.55 (dd, 1H), 7.68 (d, 1H), 7.96 (dd, 1H), 8.07-8.13 (m, 3H),8.43 (s, 1H), 8.47 (d, 1H), 8.52 (d, 1H), 8.56 (s, 1H), 8.92 (d, 1H),9.38 (s, 1H).

Example 21-1101-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.06 minutes);

MASS (ESI, Pos.): 615 (M+H)⁺.

Example 21-1111-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(3-pyridinyl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.89 minutes);

MASS (ESI, Pos.): 612 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 6.63 (d, 1H), 7.12-7.19 (m, 2H),7.52-7.60 (m, 2H), 7.75 (dd, 1H), 7.90 (dt, 1H), 8.07-8.13 (m, 2H), 8.22(s, 1H), 8.28 (d, 1H), 8.38 (s, 1H), 8.62-8.70 (m, 5H), 9.26 (s, 1H).

Example 21-1121-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)-4-(trifluoromethyl)phenyl]urea

TLC:Rf 0.50 (Ethyl acetate);

¹H-NMR (DMSO-d₆): δ 3.32 (s, 6H), 3.41 (s, 3H), 6.63 (d, 1H), 7.15-7.22(m, 2H), 8.04-8.15 (m, 4H), 8.39 (s, 1H), 8.48-8.55 (m, 1H), 8.65 (d,1H), 8.73 (s, 2H), 9.03 (s, 1H), 10.33 (s, 1H).

Example 21-1131-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)-4-(trifluoromethyl)phenyl]urea

TLC:Rf 0.37 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.31-2.42 (m, 2H), 3.41 (s, 3H), 4.12-4.18 (m, 4H),6.24 (d, 1H), 7.10-7.19 (m, 2H), 8.01-8.11 (m, 4H), 8.37 (s, 1H), 8.49(d, 1H), 8.63 (d, 1H), 8.73 (s, 2H), 9.02 (s, 1H), 10.32 (s, 1H).

Example 21-1141-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(5-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.89 minutes);

MASS (ESI, Pos.): 626 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.38 (s, 3H), 3.19 (s, 6H), 6.63 (d, 1H), 7.13-7.19(m, 2H), 7.44-7.53 (m, 2H), 7.69-7.73 (m, 1H), 8.07-8.13 (m, 2H), 8.18(s, 1H), 8.38 (s, 1H), 8.42-8.45 (m, 2H), 8.51-8.54 (m, 1H), 8.63-8.67(m, 3H), 9.25 (s, 1H).

Example 21-1151-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(5-methyl-3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 0.90 minutes);

MASS (ESI, Pos.): 638 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.47 (m, 5H), 4.12-4.19 (m, 4H), 6.24 (d, 1H),7.12-7.18 (m, 2H), 7.43-7.53 (m, 2H), 7.70-7.73 (m, 1H), 8.04-8.10 (m,2H), 8.18 (s, 1H), 8.37 (s, 1H), 8.42-8.46 (m, 2H), 8.51-8.54 (m, 1H),8.63-8.66 (m, 3H), 9.26 (s, 1H).

Example 21-1161-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′,4′-dimethyl-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 1.19 minutes);

MASS (ESI, Pos.): 651 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.30 (s, 6H), 2.33-2.44 (m, 2H), 4.11-4.19 (m, 4H),6.24 (d, 1H), 7.12-7.18 (m, 3H), 7.20-7.22 (m, 1H), 7.28-7.46 (m, 3H),8.00 (s, 1H), 8.04-8.10 (m, 2H), 8.37 (s, 1H), 8.45-8.48 (m, 1H),8.62-8.66 (m, 3H), 9.42 (s, 1H).

Example 21-1171-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.15 minutes);

MASS (ESI, Pos.): 637 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32-2.43 (m, 5H), 4.11-4.20 (m, 4H), 6.24 (d, 1H),7.12-7.18 (m, 2H), 7.20-7.32 (m, 3H), 7.37-7.48 (m, 3H), 8.00-8.11 (m,3H), 8.37 (s, 1H), 8.43-8.46 (m, 1H), 8.63-8.66 (m, 3H), 9.41 (s, 1H).

Example 21-1181-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.86 minutes);

MASS (ESI, Pos.): 545 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 3.28 (s, 3H), 6.63 (d, 1H), 7.14-7.20(m, 2H), 7.27 (td, 1H), 7.65-7.71 (m, 1H), 7.85 (dd, 1H), 8.09-8.18 (m,3H), 8.39 (s, 1H), 8.65 (d, 1H), 8.72-8.78 (m, 3H), 10.09 (s, 1H).

Example 21-1191-(2-{4-[5-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.92 minutes);

MASS (ESI, Pos.): 599 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.93 (d, 3H), 3.38 (s, 3H), 6.27 (d, 1H), 7.17 (d,2H), 7.56-7.68 (m, 2H), 8.03-8.18 (m, 3H), 8.32 (s, 1H), 8.47 (d, 1H),8.63 (s, 1H), 8.73 (s, 2H), 8.96 (s, 1H), 10.28 (s, 1H).

Example 21-1201-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(ethylsulfonyl)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.24 (Hexane:Ethyl Acetate=1:4);

¹H-NMR (DMSO-d₆): δ 1.14 (t, 3H), 3.18 (s, 6H), 3.45 (q, 2H), 6.61 (d,1H), 7.16 (d, 2H), 7.62 (dd, 1H), 8.01 (d, 1H), 8.10 (d, 2H), 8.38 (s,1H), 8.61-8.67 (m, 2H), 8.72 (s, 2H), 8.99 (s, 1H), 10.28 (s, 1H).

Example 21-1211-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(methylthio)-5-(trifluoromethyl)phenyl]urea

TLC:Rf 0.28 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.53 (s, 3H), 3.19 (s, 6H), 6.62 (d, 1H), 7.16 (d,2H), 7.40 (dd, 1H), 7.54 (d, 1H), 8.10 (d, 2H), 8.19 (d, 1H), 8.38 (s,1H), 8.42 (s, 1H), 8.63 (d, 1H), 8.70 (s, 2H), 9.62 (s, 1H).

Example 21-1221-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[5-fluoro-2-(methylsulfonyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.93 minutes);

MASS (ESI, Pos.): 599 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.20 (s, 6H), 3.30 (s, 3H), 6.63 (d, 1H), 7.09-7.21(m, 3H), 7.91 (dd, 1H), 8.08-8.17 (m, 3H), 8.39 (s, 1H), 8.65 (d, 1H),8.72 (s, 2H), 8.93 (s, 1H), 10.26 (s, 1H).

Example 21-1232-{[(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)carbamoyl]amino}-N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 1.04 minutes);

MASS (ESI, Pos.): 642 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.75 (s, 6H), 3.19 (s, 6H), 6.63 (d, 1H), 7.17 (d,2H), 7.59 (dd, 1H), 7.94 (d, 1H), 8.11 (d, 2H), 8.39 (s, 1H), 8.61 (d,1H), 8.65 (d, 1H), 8.72 (s, 2H), 8.98 (s, 1H), 10.28 (s, 1H).

Example 21-1242-{[(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)carbamoyl]amino}-N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 1.06 minutes);

MASS (ESI, Pos.): 654 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.31-2.44 (m, 2H), 2.75 (s, 6H), 4.15 (t, 4H), 6.24(d, 1H), 7.16 (d, 2H), 7.60 (dd, 1H), 7.95 (d, 1H), 8.08 (d, 2H), 8.38(s, 1H), 8.61 (d, 1H), 8.64 (d, 1H), 8.72 (s, 2H), 8.98 (s, 1H), 10.28(s, 1H).

Example 21-1252-{[(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)carbamoyl]amino}-4-fluoro-N,N-dimethylbenzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 0.98 minutes);

MASS (ESI, Pos.): 592 (M+H)⁺.

Example 21-1261-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-(hydroxymethyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.04 minutes);

MASS (ESI, Pos.): 641 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.19 (s, 6H), 4.58 (d, 2H), 5.28 (t, 1H), 6.63 (d,1H), 7.15 (d, 2H), 7.31 (d, 1H), 7.36 (s, 1H), 7.37-7.56 (m, 4H), 8.04(s, 1H), 8.10 (d, 2H), 8.38 (s, 1H), 8.42 (s, 1H), 8.62-8.68 (m, 3H),9.39 (s, 1H).

Example 21-1271-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-(hydroxymethyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.05 minutes);

MASS (ESI, Pos.): 653 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.37 (quint, 2H), 4.15 (t, 4H), 4.58 (d, 2H), 5.30(t, 1H), 6.24 (s, 1H), 7.14 (d, 2H), 7.24-7.56 (m, 6H), 8.02-8.09 (m,3H), 8.37 (s, 1H), 8.42 (s, 1H), 8.60-8.63 (m, 3H), 9.38 (s, 1H).

Example 21-1281-(2-{4-[5-(1-azetidinyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-(hydroxyethyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.08 minutes);

MASS (ESI, Pos.): 667 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.36 (d, 3H), 2.37 (quint, 2H), 4.15 (t, 4H),4.75-4.82 (m, 1H), 5.21 (d, 1H), 6.24 (d, 1H), 7.14 (d, 2H), 7.29-7.34(m, 1H), 7.38-7.53 (m, 5H), 8.02-8.10 (m, 3H), 8.37 (s, 2H), 8.62-8.64(m, 3H), 9.37 (s, 1H).

Example 21-1291-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-(2-hydroxy-2-propanyl)-4-(trifluoromethyl)-2-biphenylyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.06 minutes);

MASS (ESI, Pos.): 669 (M+H).

Example 21-1301-[3′-(hydroxymethyl)-4-(trifluoromethyl)-2-biphenylyl]-3-{2-[4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.02 minutes);

MASS (ESI, Pos.): 612 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.60 (s, 3H), 4.58 (d, 2H), 5.28 (t, 1H), 6.98 (d,1H), 7.23 (d, 2H), 7.30 (d, 1H), 7.34-7.56 (m, 5H), 8.05 (s, 1H), 8.14(d, 2H), 8.42 (d, 1H), 8.65 (s, 2H), 8.66 (s, 1H), 9.00 (d, 1H), 9.40(s, 1H).

Example 21-1311-[3′-(1-hydroxyethyl)-4-(trifluoromethyl)-2-biphenylyl]-3-{2-[4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.04 minutes);

MASS (ESI, Pos.): 626 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.36 (d, 3H), 2.60 (s, 3H), 4.74-4.83 (m, 1H), 5.21(d, 1H), 6.98 (d, 1H), 7.23 (d, 2H), 7.27-7.35 (m, 1H), 7.39-7.52 (m,5H), 8.07 (s, 1H), 8.10-8.17 (m, 2H), 8.37 (s, 1H), 8.64 (s, 2H), 8.66(s, 1H), 9.00 (d, 1H), 9.38 (s, 1H).

Example 21-1321-[3′-(2-hydroxy-2-propanyl)-4-(trifluoromethyl)-2-biphenylyl]-3-{2-[4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.06 minutes);

MASS (ESI, Pos.): 640 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.45 (s, 6H), 2.60 (s, 3H), 5.07 (s, 1H), 6.98 (d,1H), 7.23 (d, 2H), 7.24-7.31 (m, 1H), 7.41-7.59 (m, 5H), 8.08 (s, 1H),8.11-8.18 (m, 2H), 8.34 (s, 1H), 8.64 (s, 2H), 8.66 (s, 1H), 9.00 (d,1H), 9.37 (s, 1H).

Example 21-1331-{2-[4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.09 minutes);

MASS (ESI, Pos.): 640 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.60 (s, 3H), 6.98 (d, 1H), 7.12 (d, 1H), 7.23 (d,2H), 7.58 (dd, 1H), 7.70 (d, 1H), 8.14 (d, 2H), 8.47 (s, 2H), 8.57 (s,1H), 8.63-8.67 (m, 3H), 9.00 (d, 1H), 9.46 (s, 1H).

Example 21-1341-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]-3-(2-{4-[5-(3-oxetanyloxy)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.97 minutes);

MASS (ESI, Pos.): 642 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.38 (s, 3H), 4.63-4.76 (m, 2H), 4.96-5.04 (m, 2H),5.76 (quint, 1H), 6.70 (d, 1H), 7.26 (d, 2H), 7.64 (d, 1H), 7.99-8.11(m, 3H), 8.59-8.64 (m, 2H), 8.75 (s, 2H), 8.93-9.03 (m, 2H), 10.29 (s,1H).

Example 22

The similar procedure as Example 7 was carried out with a correspondingamine compound produced with 6-chloroimidazo[1,2-b]pyridazine in placeof Example 19 produced with 5-chloropyrazolo[1,5-a]pyrimidine, and thecompound produced in Example 3 or a corresponding carbamate orisocyanate compound in place of the compound produced in Example 3 togive the present compounds having the following physicalcharacteristics.

Example 22-11-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(6-(azetidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.50 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.08 (t, 4H), 6.64-6.68 (m, 2H),7.27 (d, 2H), 7.51 (d, 1H), 7.74 (d, 1H), 7.88 (d, 1H), 7.95 (s, 2H),8.21 (d, 2H), 8.40 (d, 1H), 8.58 (s, 1H), 8.69 (s, 2H), 9.69 (s, 1H),9.95 (s, 1H).

Example 22-21-(2-(4-(6-(azetidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.52 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.08 (t, 4H), 6.66 (d, 1H),7.24-7.27 (m, 2H), 7.47-7.58 (m, 3H), 7.87-7.95 (m, 3H), 8.20-8.23 (m,3H), 8.38 (s, 1H), 8.65-8.68 (m, 4H), 9.24 (s, 1H).

Example 22-31-(2-(4-(6-(azetidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.28 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.33-2.43 (m, 2H), 4.06-4.12 (m, 4H), 6.67 (d, 1H),7.25-7.36 (m, 3H), 7.52 (t, 1H), 7.62 (d, 1H), 7.90 (d, 1H), 7.96-7.99(m, 2H), 8.19-8.26 (m, 2H), 8.73 (s, 2H), 8.99 (s, 1H), 9.31 (s, 1H).

Example 22-41-(2-(4-(6-(azetidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-phenyl-5-(trifluoromethyl)pyridin-3-yl)urea

TLC:Rf 0.34 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 2.33-2.43 (m, 2H), 4.06-4.11 (m, 4H), 6.68 (d, 1H),7.25-7.29 (m, 2H), 7.53-7.61 (m, 3H), 7.64-7.69 (m, 2H), 7.90 (d, 1H),7.97 (s, 1H), 8.20-8.25 (m, 2H), 8.43 (s, 1H), 8.69 (s, 2H), 8.72-8.75(m, 1H), 8.76-8.79 (m, 1H), 9.47 (s, 1H).

Example 22-51-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.59 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.96-2.01 (m, 4H), 3.47-3.52 (m, 4H), 6.87 (d, 1H),7.25-7.28 (m, 2H), 7.50-7.58 (m, 3H), 7.85-7.94 (m, 3H), 8.23-8.28 (m,3H), 8.39 (s, 1H), 8.65-8.68 (m, 4H), 9.24 (s, 1H).

Example 22-61-(2-(4-(6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.40 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 1.96-2.02 (m, 4H), 3.47-3.54 (m, 4H), 6.88 (d, 1H),7.26-7.36 (m, 3H), 7.53 (t, 1H), 7.61 (dd, 1H), 7.87 (d, 1H), 7.95-7.99(m, 2H), 8.28 (d, 2H), 8.73 (s, 2H), 8.98 (s, 1H), 9.31 (s, 1H).

Example 22-71-(2-phenyl-5-(trifluoromethyl)pyridin-3-yl)-3-(2-(4-(6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.50 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.96-2.03 (m, 4H), 3.46-3.55 (m, 4H), 6.87 (d, 1H),7.27 (d, 2H), 7.52-7.69 (m, 5H), 7.86 (d, 1H), 7.94 (s, 1H), 8.26 (d,2H), 8.40-8.44 (m, 1H), 8.67-8.78 (m, 4H), 9.45 (s, 1H).

Example 22-81-(2-(4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.27 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 4.01 (s, 3H), 6.95 (d, 1H), 7.29-7.32 (m, 2H),7.47-7.58 (m, 3H), 7.87-7.91 (m, 1H), 8.07-8.10 (m, 2H), 8.20-8.24 (m,3H), 8.39 (s, 1H), 8.65-8.69 (m, 4H), 9.25 (s, 1H).

Example 22-91-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.68 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.68 (t, 1H), 6.95 (d, 1H), 7.31-7.34(m, 2H), 7.52 (dd, 1H), 7.75 (d, 1H), 7.96 (d, 1H), 8.07-8.10 (m, 2H),8.21-8.24 (m, 2H), 8.41 (d, 1H), 7.58 (d, 1H), 8.71 (s, 2H), 9.70 (s,1H), 9.97 (s, 1H).

Example 22-101-(2-(4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.59 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.95 (d, 1H), 7.31-7.34 (m, 3H), 7.51(t, 1H), 7.62 (d, 1H), 7.98 (s, 1H), 8.07-8.10 (m, 2H), 8.21-8.24 (m,2H), 8.74 (s, 2H), 8.99 (s, 1H), 9.31 (s, 1H).

Example 22-111-(2-(4-(6-(2-hydroxypropan-2-yl)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.20 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.59 (s, 6H), 5.61 (s, 1H), 7.31-7.38 (m, 3H),7.50-7.64 (m, 3H), 7.97-8.00 (m, 1H), 8.17 (d, 1H), 8.22-8.28 (m, 3H),8.75 (s, 2H), 9.00 (s, 1H), 9.32 (s, 1H).

Example 22-121-(2-(4-(6-(1-hydroxyethyl)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.19 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.49 (d, 3H), 4.85-4.93 (m, 1H), 5.74 (d, 1H),7.31-7.37 (m, 3H), 7.41 (d, 1H), 7.52 (t, 1H), 7.60-7.65 (m, 1H),7.97-8.00 (m, 1H), 8.18-8.25 (m, 4H), 8.75 (s, 2H), 9.00 (s, 1H), 9.32(s, 1H).

Example 22-131-(2-(4-(6-((2-hydroxy-2-methylpropyl)amino)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.35 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.19 (s, 6H), 3.27 (d, 2H), 4.57 (s, 1H), 6.87-6.90(m, 2H), 7.26-7.34 (m, 3H), 7.51 (t, 1H), 7.62 (d, 1H), 7.73 (d, 1H),7.85 (s, 1H), 7.97 (s, 1H), 8.20-8.25 (m, 2H), 8.73 (s, 2H), 8.98 (s,1H), 9.31 (s, 1H).

Example 22-141-(2-(4-(imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.50 (Ethyl Acetate:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 7.26-7.34 (m, 3H), 7.47-7.58 (m, 3H), 7.87-7.93 (m,1H), 8.15-8.28 (m, 5H), 8.38 (s, 1H), 8.63-8.70 (m, 5H), 9.24 (s, 1H).

Example 22-151-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.45 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.27-7.38 (m, 4H), 7.59-7.65 (m, 1H), 7.74 (d, 1H),8.10 (s, 1H), 8.16-8.28 (m, 4H), 8.58 (s, 1H), 8.63-8.73 (m, 4H), 9.66(s, 1H).

Example 22-161-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.38 (Hexane:Ethyl Acetate=1:2);

¹H-NMR (DMSO-d₆): δ 6.67-6.72 (m, 1H), 7.26-7.40 (m, 3H), 7.50-7.57 (m,1H), 7.75 (d, 1H), 7.95-8.00 (m, 1H), 8.16-8.30 (m, 4H), 8.40-8.45 (m,1H), 8.59 (s, 1H), 8.64-8.68 (m, 1H), 8.70 (s, 2H), 9.70 (s, 1H), 9.96(s, 1H).

Example 22-171-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-(imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.27 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.28-7.43 (m, 4H), 7.74 (d, 1H), 8.16-8.27 (m, 4H),8.56 (dd, 1H), 8.64 (dd, 1H), 8.75 (s, 2H), 8.78 (s, 1H), 9.72 (s, 1H).

Example 22-181-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(4-(imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.30 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.27-7.54 (m, 5H), 8.16-8.27 (m, 4H), 8.53 (dd, 1H),8.63 (dd, 1H), 8.75 (s, 2H), 9.08 (s, 1H), 9.31 (s, 1H).

Example 22-191-(2-(4-(imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-methyl-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.43 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 2.32 (s, 3H), 7.27-7.41 (m, 6H), 8.17-8.26 (m, 6H),8.64 (dd, 1H), 8.75 (s, 2H).

Example 22-201-(2-(4-(imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.47 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.27-7.36 (m, 4H), 7.51 (t, 1H), 7.62 (d, 1H), 7.97(s, 1H), 8.17-8.26 (m, 4H), 8.64 (d, 1H), 8.74 (s, 2H), 8.99 (s, 1H),9.31 (s, 1H).

Example 22-211-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(4-(imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.22 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.22-7.37 (m, 4H), 7.62 (d, 1H), 7.70 (s, 1H),8.15-8.27 (m, 4H), 8.26 (d, 1H), 8.63 (dd, 1H), 8.73 (s, 2H), 9.12 (s,1H), 9.52 (s, 1H).

Example 22-221-(2-(4-(6-(azetidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.57 (Ethyl Acetate:Methanol=9:1; CHROMATOREX NH TLC PLATE);

¹H-NMR (DMSO-d₆): δ 2.32-2.42 (m, 2H), 4.08 (t, 4H), 6.67 (d, 1H),7.27-7.30 (m, 2H), 7.69 (dd, 1H), 7.88-7.91 (m, 2H), 7.97 (s, 1H),8.21-8.24 (m, 2H), 8.44 (d, 1H), 8.75 (s, 2H), 8.82 (br s, 1H), 9.76(brs, 1H).

Example 22-231-(2-chloro-4-(trifluoromethyl)phenyl)-3-(2-(4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.53 (Ethyl Acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.95 (d, 1H), 7.32-7.35 (m, 2H), 7.69(dd, 1H), 7.89 (d, 1H), 8.07-8.10 (m, 2H), 8.21-8.24 (m, 2H), 8.43 (d,1H), 8.76 (s, 2H), 8.80 (s, 1H), 9.78 (s, 1H).

Example 22-241-(2-chloro-4-(trifluoromethyl)phenyl)-3-(2-(4-(imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.33 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.31 (dd, 1H), 7.36 (d, 2H), 7.68 (dd, 1H),7.88-7.92 (m, 1H), 8.17-8.28 (m, 4H), 8.43 (d, 1H), 8.64 (dd, 1H), 8.75(s, 2H), 8.79 (s, 1H), 9.78 (s, 1H).

Example 22-251-(2-(4-(imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(4-(trifluoromethyl)phenyl)urea

TLC:Rf 0.20 (Hexane:Ethyl Acetate=1:3);

¹H-NMR (DMSO-d₆): δ 7.28 (dd, 1H), 7.35 (d, 2H), 7.61-7.69 (m, 4H),8.16-8.28 (m, 4H), 8.64 (d, 1H), 8.74 (s, 2H), 8.99 (s, 1H), 9.37 (s,1H).

Example 22-261-(2-(4-(6-(azetidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3,5-difluorophenyl)urea

TLC:Rf 0.25 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 6.76-6.85 (m, 1H), 7.19 (dd, 2H), 7.27-7.35 (m, 3H),8.17-8.27 (m, 4H), 8.64 (dd, 1H), 8.72 (s, 2H), 9.15 (s, 1H), 9.46 (s,1H).

Example 22-271-(6-(4-(imidazo[1,2-b]pyridazin-3-yl)phenoxy)pyridin-3-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.51 (Ethyl Acetate);

¹H-NMR (DMSO-d₆): δ 7.07 (d, 1H), 7.22-7.31 (m, 4H), 7.50 (t, 1H), 7.59(d, 1H), 7.97-8.00 (m, 1H), 8.03 (dd, 1H), 8.14-8.25 (m, 5H), 8.63 (dd,1H), 8.90 (s, 1H), 9.14 (s, 1H).

Example 22-281-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 96% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 602 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.65 (s, 3H), 4.01 (s, 3H), 6.45 (d, 1H), 6.95 (d,1H), 7.30-7.33 (m, 2H), 7.46-7.52 (m, 2H), 7.62 (d, 1H), 8.07-8.23 (m,5H), 8.56 (s, 1H), 8.69 (s, 2H), 9.50 (s, 1H).

Example 22-291-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 0.94 minutes);

MASS (ESI, Pos.): 602 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.37 (s, 3H), 4.02 (s, 3H), 6.45 (d, 1H), 6.95 (d,1H), 7.30-7.35 (m, 2H), 7.49 (dd, 1H), 7.70 (d, 1H), 8.07-8.11 (m, 2H),8.23-8.25 (m, 2H), 8.28 (d, 1H), 8.57 (d, 1H), 8.71 (s, 2H), 9.81 (s,1H), 9.93 (s, 1H).

Example 22-301-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 96% (Retention Time: 0.95 minutes);

MASS (ESI, Pos.): 602 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.14 (s, 3H), 4.02 (s, 3H), 6.95 (d, 1H), 7.32 (d,2H), 7.49 (dd, 1H), 7.70 (d, 1H), 7.79 (s, 1H), 8.07-8.11 (m, 2H),8.19-8.24 (m, 3H), 8.57 (d, 1H), 8.71 (s, 2H), 9.84 (s, 1H), 9.98 (s,1H).

Example 22-311-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-pyridinyl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.78 minutes);

MASS (ESI, Pos.): 599 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.01 (s, 3H), 6.95 (d, 1H), 7.31 (d, 2H), 7.54-7.57(m, 2H), 7.76 (dd, 1H), 7.88-7.92 (m, 1H), 8.07-8.10 (m, 2H), 8.20-8.29(m, 4H), 8.65-8.69 (m, 4H), 9.30 (s, 1H).

Example 22-321-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-methyl-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 536 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32 (s, 3H), 4.02 (s, 3H), 6.95 (d, 1H), 7.29-7.34(m, 3H), 7.42 (d, 1H), 8.08-8.11 (m, 2H), 8.20-8.25 (m, 2H), 8.28 (s,1H), 8.38 (s, 1H), 8.75 (s, 2H), 9.34 (s, 1H).

Example 22-331-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.97 minutes);

MASS (ESI, Pos.): 656 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.01 (s, 3H), 6.93 (d, 1H), 7.12 (s, 1H), 7.31 (d,2H), 7.58 (d, 1H), 7.70 (d, 1H), 8.07-8.10 (m, 2H), 8.21 (d, 2H), 8.47(s, 2H), 8.59 (s, 1H), 8.67 (s, 2H), 9.49 (s, 1H).

Example 22-341-{2-[4-(6-ethoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 0.86 minutes);

MASS (ESI, Pos.): 613 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.41 (t, 3H), 4.40 (q, 2H), 6.92 (d, 1H), 7.28-7.32(m, 2H), 7.47-7.58 (m, 3H), 7.87-7.91 (m, 1H), 8.05-8.09 (m, 2H),8.16-8.20 (m, 2H), 8.24 (s, 1H), 8.38 (s, 1H), 8.64-8.68 (m, 4H), 9.24(s, 1H).

Example 22-351-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 0.79 minutes);

MASS (ESI, Pos.): 641 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.70 (dd, 2H), 4.95 (t, 2H), 5.62-5.71 (m, 1H), 7.02(d, 1H), 7.32-7.36 (m, 2H), 7.36-7.59 (m, 3H), 7.87-7.91 (m, 1H),8.06-8.10 (m, 3H), 8.15 (d, 1H), 8.25 (s, 1H), 8.39 (s, 1H), 8.65-8.69(m, 4H), 9.26 (s, 1H).

Example 22-361-{2-[4-(6-methylimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.76 minutes);

MASS (ESI, Pos.): 583 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.59 (s, 3H), 7.19 (d, 1H), 7.29-7.34 (m, 2H),7.47-7.58 (m, 3H), 7.87-7.91 (m, 1H), 8.09 (d, 1H), 8.16-8.24 (m, 4H),8.39 (s, 1H), 8.64-8.69 (m, 4H), 9.25 (s, 1H).

Example 22-371-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

TLC:Rf 0.31 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 4.70 (dd, 2H), 4.96 (dd, 2H), 5.63-5.71 (m, 1H),7.03 (d, 1H), 7.34-7.55 (m, 4H), 8.06-8.13 (m, 3H), 8.15 (d, 1H), 8.53(dd, 1H), 8.76 (s, 2H), 9.13 (s, 1H), 9.32 (s, 1H).

Example 22-381-[3′-(2-hydroxy-2-propanyl)-4-(trifluoromethyl)-2-biphenylyl]-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.94 minutes);

MASS (ESI, Pos.): 698 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.45 (s, 6H), 4.70 (dd, 2H), 4.95 (dd, 2H), 5.07 (s,1H), 5.61-5.72 (m, 1H), 7.02 (d, 1H), 7.29 (d, 1H), 7.35 (d, 2H),7.41-7.60 (m, 5H), 8.03-8.19 (m, 5H), 8.34 (s, 1H), 8.67 (s, 2H), 9.39(s, 1H).

Example 22-391-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 98% (Retention Time: 0.91 minutes);

MASS (ESI, Pos.): 588 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.01 (s, 3H), 6.65-6.66 (m, 1H), 6.95 (d, 1H), 7.32(d, 2H), 7.75 (d, 1H), 7.83 (s, 1H), 7.94 (d, 1H), 8.07-8.11 (m, 2H),8.22 (d, 2H), 8.41-8.44 (m, 2H), 8.71 (s, 2H), 9.57 (s, 1H), 9.98 (s,1H).

Example 22-401-[3-(difluoromethyl)phenyl]-3-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.77 minutes);

MASS (ESI, Pos.): 504 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.82-7.19 (m, 3H), 7.31-7.35 (m, 2H),7.42 (t, 1H), 7.52 (d, 1H), 7.78 (s, 1H), 8.08-8.11 (m, 2H), 8.20-8.25(m, 2H), 8.74 (s, 2H), 8.92 (s, 1H), 9.17 (s, 1H).

Example 22-411-[2-chloro-5-(trifluoromethyl)phenyl]-3-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.91 minutes);

MASS (ESI, Pos.): 556 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.95 (d, 1H), 7.31-7.36 (m, 2H), 7.40(dd, 1H), 7.73 (d, 1H), 8.08-8.11 (m, 2H), 8.21-8.25 (m, 2H), 8.57 (d,1H), 8.76 (s, 2H), 8.79 (s, 1H), 9.72 (s, 1H).

Example 22-421-[2-fluoro-5-(trifluoromethyl)phenyl]-3-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 540 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.95 (d, 1H), 7.31-7.36 (m, 2H),7.38-7.54 (m, 2H), 8.08-8.11 (m, 2H), 8.20-8.25 (m, 2H), 8.53 (dd, 1H),8.75 (s, 2H), 9.10 (d, 1H), 9.31 (s, 1H).

Example 22-431-(2,5-dichlorophenyl)-3-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.89 minutes);

MASS (ESI, Pos.): 522 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.95 (d, 1H), 7.11 (dd, 1H), 7.31-7.35(m, 2H), 7.50 (d, 1H), 8.07-8.10 (m, 2H), 8.20-8.26 (m, 3H), 8.64 (s,1H), 8.74 (s, 2H), 9.68 (s, 1H).

Example 22-441-(2,4-dichlorophenyl)-3-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.89 minutes);

MASS (ESI, Pos.): 522 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.95 (d, 1H), 7.31-7.35 (m, 2H), 7.39(dd, 1H), 7.64 (d, 1H), 8.07-8.11 (m, 2H), 8.14 (d, 1H), 8.20-8.25 (m,2H), 8.58 (s, 1H), 8.74 (s, 2H), 9.60 (s, 1H).

Example 22-451-(2,5-difluorophenyl)-3-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.79 minutes);

MASS (ESI, Pos.): 490 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.81-6.90 (m, 1H), 6.95 (d, 1H),7.26-7.35 (m, 3H), 7.94-8.00 (m, 1H), 8.08-8.12 (m, 2H), 8.20-8.25 (m,2H), 8.74 (s, 2H), 8.97 (s, 1H), 9.28 (s, 1H).

Example 22-461-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 99% (Retention Time: 0.86 minutes);

MASS (ESI, Pos.): 603 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.38 (s, 3H), 4.01 (s, 3H), 6.95 (d, 1H), 7.30-7.34(m, 2H), 7.59 (dd, 1H), 7.70 (d, 1H), 8.07-8.10 (m, 2H), 8.20-8.24 (m,2H), 8.39 (s, 1H), 8.60 (s, 1H), 8.69 (s, 2H), 8.76 (s, 1H), 9.70 (s,1H).

Example 22-471-[5-chloro-2-(1H-pyrazol-1-yl)phenyl]-3-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.88 minutes);

MASS (ESI, Pos.): 554 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.01 (s, 3H), 6.61-6.63 (m, 1H), 6.94 (d, 1H), 7.22(dd, 1H), 7.30-7.34 (m, 2H), 7.51 (d, 1H), 7.89 (d, 1H), 8.07-8.10 (m,2H), 8.19-8.24 (m, 2H), 8.26 (d, 1H), 8.27 (d, 1H), 8.69 (s, 2H), 9.37(s, 1H), 9.89 (s, 1H).

Example 22-481-[5-chloro-2-(3-pyridinyl)phenyl]-3-{2-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 77% (Retention Time: 0.75 minutes);

MASS (ESI, Pos.): 565 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.02 (s, 3H), 6.95 (d, 1H), 7.22-7.34 (m, 4H), 7.54(dd, 1H), 7.80-7.85 (m, 1H), 8.07-8.23 (m, 6H), 8.59-8.66 (m, 4H), 9.20(brs, 1H).

Example 22-491-{6-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-3-pyridinyl}-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 98% (Retention Time: 0.83 minutes);

MASS (ESI, Pos.): 598 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.00 (s, 3H), 6.94 (d, 1H), 7.05 (d, 1H), 7.18-7.23(m, 2H), 7.45-7.59 (m, 3H), 7.87-7.91 (m, 1H), 8.00 (dd, 1H), 8.06-8.21(m, 6H), 8.42 (s, 1H), 8.64-8.69 (m, 2H), 9.18 (s, 1H).

Example 22-501-{6-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-3-pyridinyl}-3-[2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.95 minutes);

MASS (ESI, Pos.): 587 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.01 (s, 3H), 6.67-6.68 (m, 1H), 6.94 (d, 1H), 7.07(d, 1H), 7.19-7.24 (m, 2H), 7.50 (dd, 1H), 7.73 (d, 1H), 7.95 (d, 1H),8.00-8.10 (m, 3H), 8.18-8.21 (m, 3H), 8.40 (d, 1H), 8.59 (s, 1H), 9.56(s, 1H), 9.83 (s, 1H).

Example 22-511-{6-[4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-3-pyridinyl}-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 1.01 minutes);

MASS (ESI, Pos.): 655 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.01 (s, 3H), 6.94 (d, 1H), 7.07 (d, 1H), 7.13 (d,1H), 7.19-7.24 (m, 2H), 7.55 (dd, 1H), 7.69 (d, 1H), 7.99 (dd, 1H),8.01-8.21 (m, 5H), 8.45-8.52 (m, 3H), 9.40 (s, 1H).

Example 22-521-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.84 minutes);

MASS (ESI, Pos.): 564 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.68-4.72 (m, 2H), 4.93-4.98 (m, 2H), 5.63-5.72 (m,1H), 7.02 (d, 1H), 7.31-7.40 (m, 3H), 7.51 (t, 1H), 7.61 (d, 1H),7.96-8.00 (m, 1H), 8.07-8.17 (m, 4H), 8.74 (s, 2H), 9.00 (s, 1H), 9.32(s, 1H).

Example 22-531-[2-chloro-5-(trifluoromethyl)phenyl]-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.90 minutes);

MASS (ESI, Pos.): 598 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.68-4.73 (m, 2H), 4.93-4.99 (m, 2H), 5.63-5.72 (m,1H), 7.03 (d, 1H), 7.35-7.43 (m, 3H), 7.73 (d, 1H), 8.07-8.17 (m, 4H),8.57 (d, 1H), 8.76 (s, 2H), 8.80 (s, 1H), 9.73 (s, 1H).

Example 22-541-[2-methyl-5-(trifluoromethyl)phenyl]-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.86 minutes);

MASS (ESI, Pos.): 578 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.32 (s, 3H), 4.67-4.74 (m, 2H), 4.93-4.99 (m, 2H),5.63-5.71 (m, 1H), 7.03 (d, 1H), 7.27-7.45 (m, 4H), 8.07-8.18 (m, 4H),8.27-8.30 (m, 1H), 8.39 (s, 1H), 8.76 (s, 2H), 9.35 (s, 1H).

Example 22-551-(2,4-dichlorophenyl)-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 564 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.67-4.74 (m, 2H), 4.92-5.00 (m, 2H), 5.63-5.72 (m,1H), 7.03 (d, 1H), 7.34-7.43 (m, 3H), 7.64 (dd, 1H), 8.06-8.19 (m, 5H),8.59 (s, 1H), 8.75 (s, 2H), 9.61 (s, 1H).

Example 22-561-(5-chloro-2-methylphenyl)-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.84 minutes);

MASS (ESI, Pos.): 544 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.22 (s, 3H), 4.70 (dd, 2H), 4.96 (dd, 2H),5.63-5.72 (m, 1H), 6.98-7.05 (m, 2H), 7.20 (d, 1H), 7.36 (d, 2H), 7.98(d, 1H), 8.05-8.19 (m, 4H), 8.27 (s, 1H), 8.75 (s, 2H), 9.31 (s, 1H).

Example 22-571-(2,5-difluorophenyl)-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 99% (Retention Time: 0.81 minutes);

MASS (ESI, Pos.): 532 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.70 (dd, 2H), 4.96 (dd, 2H), 5.62-5.72 (m, 1H),6.81-6.92 (m, 1H), 7.03 (d, 1H), 7.23-7.32 (m, 1H), 7.38 (d, 2H),7.93-8.01 (m, 1H), 8.04-8.19 (m, 4H), 8.75 (s, 2H), 8.98 (s, 1H), 9.29(s, 1H).

Example 22-581-[5-methyl-2-(methylsulfonyl)phenyl]-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.77 minutes);

MASS (ESI, Pos.): 588 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 2.37 (s, 3H), 3.24 (s, 3H), 4.71 (dd, 2H), 4.96 (dd,2H), 5.62-5.72 (m, 1H), 7.03 (d, 1H), 7.12 (d, 1H), 7.37 (d, 2H), 7.73(d, 1H), 7.99 (s, 1H), 8.05-8.20 (m, 4H), 8.73 (s, 1H), 8.77 (s, 2H),10.13 (s, 1H).

Example 22-591-[5-chloro-2-(methylsulfonyl)phenyl]-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.83 minutes);

MASS (ESI, Pos.): 608 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.32 (s, 3H), 4.70 (dd, 2H), 4.95 (dd, 2H),5.63-5.71 (m, 1H), 7.03 (d, 1H), 7.23-7.31 (m, 3H), 7.85 (d, 1H),8.03-8.19 (m, 4H), 8.33 (d, 1H), 8.77 (s, 2H), 8.88 (s, 1H), 10.14 (s,1H).

Example 22-601-[5-fluoro-2-(methylsulfonyl)phenyl]-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 99% (Retention Time: 0.79 minutes);

MASS (ESI, Pos.): 592 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.32 (s, 3H), 4.71 (dd, 2H), 4.96 (dd, 2H),5.62-5.72 (m, 1H), 7.03 (d, 1H), 7.20-7.30 (m, 1H), 7.37 (d, 2H), 7.92(dd, 1H), 8.03-8.20 (m, 5H), 8.76 (s, 2H), 8.95 (s, 1H), 10.30 (s, 1H).

Example 22-611-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 98% (Retention Time: 0.87 minutes);

MASS (ESI, Pos.): 642 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.39 (s, 3H), 4.70 (dd, 2H), 4.95 (dd, 2H),5.62-5.73 (m, 1H), 7.03 (d, 1H), 7.37 (d, 2H), 7.64 (d, 1H), 8.03-8.20(m, 5H), 8.63 (s, 1H), 8.77 (s, 2H), 8.98 (s, 1H), 10.32 (s, 1H).

Example 22-621-[2-(methylsulfonyl)phenyl]-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 93% (Retention Time: 0.73 minutes);

MASS (ESI, Pos.): 574 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 3.28 (s, 3H), 4.70 (dd, 2H), 4.96 (dd, 2H),5.62-5.73 (m, 1H), 7.03 (d, 1H), 7.25-7.33 (m, 1H), 7.37 (d, 2H),7.62-7.72 (m, 1H), 7.85 (dd, 1H), 8.04-8.20 (m, 5H), 8.77 (s, 3H), 10.14(s, 1H).

Example 22-632-[({2-[4-(6-ethoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}carbamoyl)amino]-N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide

Purity (LC-MS/ELSD): 100% (Retention Time: 0.99 minutes);

MASS (ESI, Pos.): 643 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.41 (t, 3H), 2.76 (s, 6H), 4.42 (q, 2H), 6.92 (d,1H), 7.33 (d, 2H), 7.60 (dd, 1H), 7.94 (d, 1H), 8.05-8.10 (m, 2H), 8.20(d, 2H), 8.61 (s, 1H), 8.75 (s, 2H), 8.99 (s, 1H), 10.31 (s, 1H).

Example 22-641-{2-[4-(6-ethoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.94 minutes);

MASS (ESI, Pos.): 614 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.41 (t, 3H), 3.38 (s, 3H), 4.42 (q, 2H), 6.93 (d,1H), 7.33 (d, 2H), 7.64 (d, 1H), 8.03-8.26 (m, 3H), 8.20 (d, 2H), 8.63(s, 1H), 8.76 (s, 2H), 8.97 (s, 1H), 10.31 (s, 1H).

Example 22-651-[5-chloro-2-(methylsulfonyl)phenyl]-3-{2-[4-(6-ethoxyimidazo[1,2-b]pyridazin-3-yl)phenoxy]-5-pyrimidinyl}urea

Purity (LC-MS/ELSD): 100% (Retention Time: 0.91 minutes);

MASS (ESI, Pos.): 580 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.43 (t, 3H), 3.32 (s, 3H), 4.45 (q, 2H), 7.26 (d,1H), 7.35-7.41 (m, 3H), 7.85 (d, 1H), 8.18 (d, 2H), 8.27 (d, 1H), 8.33(d, 1H), 8.40 (s, 1H), 8.77 (s, 2H), 8.89 (s, 1H), 10.33 (s, 1H).

Example 22-661-[3′-(hydroxymethyl)-4-(trifluoromethyl)-2-biphenylyl]-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 99% (Retention Time: 1.07 minutes);

MASS (ESI, Pos.): 670 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 4.58 (d, 2H), 4.70 (dd, 2H), 4.95 (dd, 2H), 5.29 (t,1H), 5.67 (quint, 1H), 7.03 (d, 1H), 7.27-7.56 (m, 8H), 8.04-8.15 (m,4H), 8.15 (d, 1H), 8.42 (d, 1H), 8.68 (s, 2H), 9.43 (s, 1H).

Example 22-671-[3′-(1-hydroxyethyl)-4-(trifluoromethyl)-2-biphenylyl]-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl]phenoxy}-5-pyrimidinyl)urea

Purity (LC-MS/ELSD): 99% (Retention Time: 0.94 minutes);

MASS (ESI, Pos.): 684 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 1.36 (d, 3H), 4.70 (dd, 2H), 4.76-4.83 (m, 1H), 4.95(dd, 2H), 5.21 (d, 1H), 5.67 (quint, 1H), 7.02 (d, 1H), 7.27-7.56 (m,8H), 8.03-8.13 (m, 4H), 8.15 (d, 1H), 8.37 (s, 1H), 8.67 (s, 2H), 9.41(s, 1H).

Example 23

The similar procedure as Example 7 was carried out with a correspondingamine compound produced with a corresponding bicyclic heterocyclecompound in place of Example 19 produced with5-chloropyrazolo[1,5-a]pyrimidine, and the compound produced in Example3 or a corresponding carbamate or isocyanate compound in place of thecompound produced in Example 3 to give the present compounds having thefollowing physical characteristics.

Example 23-11-(2-(4-(6-methoxyimidazo[1,2-a]pyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.52 (Ethyl acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 3.81 (s, 3H), 7.10 (dd, 1H), 7.30-7.37 (m, 3H), 7.52(t, 1H), 7.54-7.65 (m, 2H), 7.71 (s, 1H), 7.73-7.77 (m, 2H), 7.98-8.03(m, 2H), 8.75 (s, 2H), 9.00 (s, 1H), 9.32 (s, 1H).

Example 23-21-(2-(4-(6-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.26 (Chloroform:Methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.48 (s, 6H), 5.30 (s, 1H), 7.30-7.43 (m, 4H),7.49-7.74 (m, 6H), 7.95-7.99 (m, 1H), 8.50-8.53 (m, 1H), 8.75 (s, 2H),9.00 (s, 1H), 9.32 (s, 1H).

Example 23-31-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(imidazo[1,2-a]pyridin-3-yl)phenoxy)pyrimidin-5-yl)urea

TLC:Rf 0.59 (Ethyl acetate:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 6.67 (t, 1H), 6.96 (t, 1H), 7.27-7.37 (m, 3H), 7.51(d, 1H), 7.64-7.77 (m, 5H), 7.95 (s, 1H), 8.41 (d, 1H), 8.55-8.58 (m,2H), 8.71 (s, 2H), 9.70 (s, 1H), 9.97 (s, 1H).

Example 23-41-(2-(4-(imidazo[1,2-a]pyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.27 (Ethyl acetate);

¹H-NMR (DMSO-d₆): δ 6.95-7.00 (m, 1H), 7.27-7.36 (m, 3H), 7.48-7.60 (m,3H), 7.64-7.72 (m, 3H), 7.77 (s, 1H), 7.88 (dt, 1H), 8.24 (s, 1H), 8.39(s, 1H), 8.56 (d, 1H), 8.65-8.69 (m, 4H), 9.25 (s, 1H).

Example 23-51-(2-(4-(imidazo[1,2-a]pyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.46 (Ethyl acetate);

¹H-NMR (DMSO-d₆): δ 6.95-7.05 (m, 1H), 7.28-7.38 (m, 4H), 7.52 (t, 1H),7.60-7.74 (m, 4H), 7.78 (s, 1H), 7.98 (s, 1H), 8.57 (d, 1H), 8.74 (s,2H), 9.02 (s, 1H), 9.34 (s, 1H).

Example 23-61-(2-(4-(imidazo[1,2-a]pyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-phenyl-5-(trifluoromethyl)pyridin-3-yl)urea

TLC:Rf 0.29 (Ethyl acetate);

¹H-NMR (DMSO-d₆): δ 6.95-7.01 (m, 1H), 7.27-7.37 (m, 3H), 7.54-7.78 (m,9H), 8.43 (s, 1H), 8.56 (d, 1H), 8.70 (s, 2H), 8.73 (s, 1H), 8.76 (d,1H), 9.48 (s, 1H).

Example 23-71-(2-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.23 (Ethyl acetate);

¹H-NMR (DMSO-d₆): δ 6.49 (d, 1H), 7.26 (d, 2H), 7.47-7.58 (m, 4H), 7.73(d, 2H), 7.90 (d, 1H), 8.19-8.25 (m, 2H), 8.39 (s, 1H), 8.49-8.51 (m,1H), 8.65-8.68 (m, 4H), 9.24 (s, 1H), 11.7 (s, 1H).

Example 23-81-(2-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)pyrimidin-5-yl)-3-(3-(trifluoromethyl)phenyl)urea

TLC:Rf 0.60 (Ethyl acetate);

¹H-NMR (DMSO-d₆): δ 6.49-6.50 (m, 1H), 7.26-7.36 (m, 3H), 7.46-7.54 (m,2H), 7.62 (d, 1H), 7.74 (d, 2H), 7.97 (s, 1H), 8.21 (s, 1H), 8.50-8.53(m, 1H), 8.73 (s, 2H), 8.98 (s, 1H), 9.31 (s, 1H), 11.7 (s, 1H).

Example 23-91-(2-(4-(6-amino-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.35 (Ethyl acetate);

¹H-NMR (DMSO-d₆): δ 5.19 (s, 2H), 6.20-6.24 (m, 1H), 6.99 (t, 1H), 7.23(d, 2H), 7.46-7.58 (m, 6H), 7.88-7.92 (m, 1H), 8.23 (s, 1H), 8.38 (s,1H), 8.63-8.68 (m, 4H), 9.23 (s, 1H), 10.9 (s, 1H).

Example 23-101-(2-(4-(imidazo[1,2-a]pyrazin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.34 (Dichloromethane:Methanol=9:1);

¹H-NMR (DMSO-d₆): δ 7.38 (d, 2H), 7.46-7.59 (m, 3H), 7.78 (d, 2H),7.85-7.91 (m, 1H), 7.92 (d, 1H), 8.06 (s, 1H), 8.24 (s, 1H), 8.38 (s,1H), 8.58-8.69 (m, 5H), 9.13 (d, 1H), 9.25 (s, 1H).

Example 23-111-(2-(4-(pyrazolo[1,5-a]pyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.29 (Ethyl acetate);

¹H-NMR (DMSO-d₆): δ 6.94 (t, 1H), 7.74-7.35 (m, 3H), 7.46-7.58 (m, 3H),7.71 (d, 2H), 7.89 (d, 1H), 7.96 (d, 1H), 8.23 (s, 1H), 8.36-8.38 (m,2H), 8.64-8.74 (m, 5H), 9.22 (s, 1H).

Example 23-121-(2-(4-(1H-pyrazolo[3,4-b]pyridin-5-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea

TLC:Rf 0.23 (Ethyl acetate);

¹H-NMR (DMSO-d₆): δ 7.29 (d, 2H), 7.47-7.58 (m, 3H), 7.79 (d, 2H),7.87-7.93 (m, 1H), 8.18-8.21 (m, 1H), 8.24 (s, 1H), 8.38 (s, 1H), 8.47(d, 1H), 8.64-8.68 (m, 4H), 8.83 (d, 1H), 9.23 (s, 1H), 13.7 (s, 1H).

Pharmacological Experiment Examples Pharmacological Experiment Example 1Measurement of TrkA Kinase-Inhibiting Activity Using HumanTrkA-Expressing Cells

TrkA kinase-inhibiting activity in cell systems was measured usingCHO-K1 cells exressing human TrkA and NFAT-bla (CellSenser™TrkA-NFAT-bla CHO-K1 cells, Invitrogen).

On the day before the assay, CellSenser™ TrkA-NFAT-bla CHO-K1 cells weresuspended in an assay medium (Opti-MEM1 Reduced Serum Medium(Invitrogen) containing 0.5% dialysed fetal bovine serum (Invitrogen),0.1 mM nonessential amino acids (Invitrogen), 1 mM sodium pyruvate(Invitrogen) and antibiotics (100 U/mL penicillin and 100 g/mLstreptomycin (Invitrogen))) and plated at a density of 2.4×10⁴ cells/40μL/well in a 96-well clear bottom plate (Corning, Catalogue No.: 3882).In some wells were added only the assay medium at 40 μL/well(Cell-free). On the day of the assay, 10 mM of the present compound(DMSO solution) was distributed in a 96-well plate (Costar, CatalogueNo.: 3363) and serially diluted with DMSO with the geometrical ratio of3. The serial dilutions were diluted with the assay medium to 100-foldto prepare a solution of the present compound with a 10-foldconcentration (DMSO concentration: 1%). To the plate where cells wereplated was added the present compound at 5 μL/well and the plate wasincubated in a CO₂ incubator with 5% CO₂, 95% Air at 37° C. for 30minutes. For a control and a blank, the assay medium containing 1% DMSOwas added at 5 μL/well in place of the solution of the present compound.Subsequently the assay medium containing NGF (Mouse 2.5 s, Natural,Invitrogen) was added to the plate at 5 μL/well (final concentration ofNGF: 50 ng/ml) and the plate was incubated in a CO₂ incubator with 5%CO₂, 95% Air at 37° C. for 5 hours. For the blank group, the assaymedium was added in place of NGF at 5 μL/well. A reporter assaydetection reagent (10 μL/well) was added to the plate which was thenincubated in the dark at room temperature for 120 minutes. The reporterassay detection reagent was prepared from LiveBLAzer™-FRET B/G LoadingKit (Invitrogen). On the Analyst GT (Molecular Devices Japan, K.K.) thewells were irradiated with excitation light at 405 nm and thefluorescence intensities at 460 nm and 530 nm were measured. The timeresolved fluorescence resonance energy transfer (TR-FRET) ratio of eachwell was calculated according to the following Equation 1:TR-FRET ratio=(A _(460x) −A _(460F))/(A _(530x) −A _(530F))  [Eq. 1]

wherein:

A_(460x): the fluorescence intensity at 460 nm of the present compound,control or blank;

A_(460F): the fluorescence intensity at 460 nm of the Cell-free;

A_(530x): the fluorescence intensity at 530 nm of the present compound,control or blank; and

A_(530F): the fluorescence intensity at 530 nm of the Cell-free.

The TR-FRET inhibition rate (%) of the present compound was calculatedaccording to the following Equation 2:Inhibition rate (%)={1−(A _(X) −A _(B))/(A _(C) −A _(B))}×100  [Eq. 2]

wherein

A_(X): the TR-FRET ratio when the present compound is added;

A_(B): the TR-FRET of the blank; and

A_(C): the TR-FRET of the control.

The IC₅₀ value by the present compound was calculated from theinhibition curve based on the inhibition rate of the present compound atrespective concentrations.

As a result, it was found that the present compounds had IC₅₀ values of0.5 μM or lower and had TrkA-inhibiting activity. IC₅₀ values of some ofthe present compounds are shown in the following Table 1 or 2.

TABLE 1 TrkA-inhibiting activity Example (IC50; μM) 7   0.001 8-1 0.0018-2 0.002 8-4 0.001 9-1 0.003 9-2 0.001 11   0.001 13-1  0.002 14-5 0.001 14-6  0.001 15-4  0.001 15-5  0.003 15-6  0.002 15-52 0.004 15-550.004 15-58 0.002 15-63 0.002 15-71 0.002 15-77 0.002 15-87 0.001 15-960.0004 15-98 0.0008  15-104 0.0005  15-105 0.004

TABLE 2 TrkA-inhibiting activity Example (IC50; μM) 21-1  0.001 21-2 0.001 21-9  0.001 21-13 0.001 21-37 0.001 21-51 0.001 21-65 0.0007 21-670.004 21-70 0.002 21-73 0.003 21-75 0.004 22-8  0.001 22-9  0.001 22-340.001 23-3  0.001 23-7  0.002 23-10 0.001 23-11 0.001 23-12 0.001

Pharmacological Experiment Example 2 Enzyme-Inhibiting Activity Test ofKinases Other than Trk (Selectivity Experiment)

A test substance (the present compound) was dissolved indimethylsulfoxide to prepare a 100-fold concentration of the testconcentration, 3 μM. The solution was further diluted to 25-fold with anassay buffer (20 mM HEPES, 0.01% Triton X-100, 2 mM DTT, pH 7.5) toobtain a test substance solution. In a similar manner a positive controlsubstance solution was prepared with a positive control substance.

A 4-times concentration solution (5 μL) of the test substance preparedwith the assay buffer, 5 μL of a 4-times concentration solution ofsubstrate/ATP/metal (Mg) and 10 μL of a 2-times concentration solutionof kinase were mixed in a well of a polypropylene 384-well plate andallowed to react at room temperature for 1 hour. The reaction wasterminated by adding 60 μL of a Termination Buffer (QuickScout ScreeningAssist MSA; Carna Biosciences). The substrate peptide and thephosphorylated peptide in the reaction solution were separated andquantified. The kinase reaction was assessed from the product ratio(P/(P+S)) calculated from the height (S) of the peak of the substratepeptide and the height (P) of the peak of the phosphorylated peptide.Other kinases used in the kinase selectivity experiments were, forexample, b-Raf and KDR. The following Table 3 indicates substrates,substrate concentrations, ATP concentrations and positive controlsubstances used in respective kinase enzyme inhibition activity tests.

TABLE 3 Substrate Kinase Name (nM) ATP (μM) Positive control b-RafMAP2K1 1 1000 ZM336372 KDR CSKtide 1000 75 Staurosporine

The inhibition rate was calculated from the average signal intensity ofthe test wells containing respective test substances provided that theaverage signal intensity of control wells each containing all reactioncomponents was 0% inhibition and the average signal intensity ofbackground wells (without addition of the enzyme) was 100% inhibition.As a result, the present compounds at a concentration of 3 M had theinhibition rates of kinases as shown in the following Table 4.

TABLE 4 Inhibition rate (%) Example b-Raf KDR 7   40 0 8-1 6.5 0 8-2 210 13-1  33 7.5 14-5  13 0 14-6  45 1.7 15-4  0 0 15-6  37 0 15-52 20 015-55 30 0 15-58 30 0 15-63 43 0 15-71 40 0 15-77 32 0 15-87 34 0 15-9622 2 15-98 23 8  15-104 53 18  15-105 26 0 21-1  36 1.5 21-2  30 1 21-3750 16 21-51 49 9 21-65 58 19 21-67 19 0 21-70 19 0 21-73 21 0 21-75 41 022-34 56 19

From this result, it is demonstrated that the present compounds show lowinhibition of kinases other than TrkA, e.g., b-Raf and KDR, whileexhibit strong inhibition of TrkA. In other words, the present compoundshave TrkA inhibition as strong as IC₅₀ of 0.5 μM or less according tothe result from Pharmacological Example 1, while the present compoundsinhibit kinases other than TrkA only at 0% to about 58% even at theconcentration of 3 μM according to the result from PharmacologicalExample 2. Thus it is demonstrated that the present compounds have highselectivity towards TrkA inhibition and have excellent kinaseselectivity.

Pharmacological Experiment Example 3 Inhibition of rat NGF-InducedVascular Hyper Permeability

TrkA-inhibiting activity of the present compound was evaluted in vivo.The present compound dissolved in a medium was orally administered(adminstered volume: 5 mL/kg) to male CD(SD)IGS rats (7- to 9-week old,Charles River laboratories Japan, Inc.) shaved on the back. A medium wasorally administered (adminstered volume: 5 mL/kg) to the control andnormal groups. After 6, 12 or 14 hours of administration, 3 μg/mL of aNGF (Mouse 2.5 s, Natural, Invitrogen) solution prepared in 0.1% BSA(Sigma-Aldrich)-containing saline was intracutaneously administered(dose; 50 μL/site) at 3 sites on the back of animals under halothaneanesthesia. For the normal group, 0.1% BSA-containing saline wasintracutaneously administered (dose; 50 μL/site) at 3 sites on the back.Immediately after intracutaneous administration, 1% Evans Blue (TokyoChemical Industriy Co., Ltd.) was administered intravenously from tail(adminstered volume: 3 mL/kg). After 10 minutes of administration, theanimals were sacrificed by bleeding due to incision of the abdominalaorta. The sites of intracutaneous administration on the back (3 sites)were excised and the skin samples were respectively transferred to thewells in a 48-well plate (Asahi Glass Co., Ltd.). Formamide (0.8mL/well) was added to the plate and the plate was sealed and incubatedovernight at 60° C. The formamide extraction solution (200 μL) wastransferred to a 96-well plate and the absorbance (wavelength: 620 nm)of Evans Blue extracted in formamide was measured on an absorbancemicroplate reader (SpectraMAX 190, Molecular Devices Japan, K.K.).Standard samples of Evans Blue dissolved in formamide (0, 0.78, 1.56,3.13, 6.25, 12.5, 25 and 50 μg/mL) were measured at the same time forthe absorance (wavelength: 620 nm) to generate a calibration curve.Based on the calibration curve and the absorbances of samples, theconcentrations of Evans Blue in the sample was calculated. Theconcentrations of Evans Blue for three skin samples collected from oneaminal were averaged to obtain the vale for the animal. The rate ofinhibition for rat NGF-induced vascular hyper permeability of thepresent compound was calculated according to the following Equation:Inhibition rate (%)={1−(A _(X) −A _(N))/(A _(C) −A _(N))}×100  [Eq. 3]

wherein

A_(X): the concentration of Evans Blue of the test compound (an averagevalue of 3 samples from one animal);

A_(N): the concentration of Evans Blue of the normal group (an averagevalue of 3 samples from one animal);

A_(C): the concentration of Evans Blue of the control group (an averagevalue of 3 samples from one animal).

As a result, the present compound (3 mg/kg; 6 hours afteradministration) had the rate of inhibition for rat NGF-induced vascularhyper permeability of about 70%, and it was found that the presentcompounds strongly inhibited vascular hyper permeability even after along period of time.

For example, some of the present compounds (1 mg/kg; 14 or 12 hoursafter administration) had inhibition rate of rat NGF-induced vascularhyper permeability as shown in the following Tables 5 and 6.

TABLE 5 Inhibition rate of vascular hyper permeability (%) Example (timeafter administration (h)) 7   97% (14 h) 8-1 94% (14 h) 8-2 100% (14 h)8-4 96% (14 h) 9-1 86% (14 h) 9-2 100% (14 h) 11   100% (14 h) 13-1 100% (14 h) 14-5  93% (14 h) 14-6  78% (12 h) 15-4  100% (14 h) 15-5 92% (14 h) 15-6  95% (14 h) 15-52 96% (14 h) 15-55 94% (14 h) 15-58 100%(14 h) 15-63 99% (14 h) 15-71 100% (14 h) 15-77 100% (14 h) 15-87 86%(14 h) 15-96 90% (14 h) 15-98 80% (14 h)  15-104 100% (14 h)  15-105100% (14 h)

TABLE 6 Inhibition rate of vascular hyper permeability (%) Example (timeafter administration (h)) 21-1  87% (14 h) 21-2  100% (14 h) 21-9  100%(14 h) 21-13 100% (12 h) 21-37 98% (14 h) 21-51 95% (14 h) 21-65 92% (14h) 21-67 90% (14 h) 21-70 100% (14 h) 21-73 92% (14 h) 21-75 100% (14 h)22-8  100% (14 h) 22-9  100% (14 h) 22-34 91% (14 h)

Pharmacological Experiment Example 4 Analgesic effect on SodiumMonoiodoacetate-Induced Model Rats

Using model rats induced with sodium monoiodoacetate (hereinafterabbreviated as MIA) (Sigma-Aldrich Japan), the present compounds wereevaluated for the analgesic effect thereof.

(1) Generation of MIA-Induced Model Rats

Under isoflurane anaesthesia, rats were shaved on around knees of righthind limbs and 25 μL solution of 120 mg/mL MIA was administered into theright hind limb knee joint using a syringe (BD Lo-Dose, BecktonDickinson Japan) with a 29 G needle. To a normal control group, 25 μL ofsaline was administered.

(2) Group Organisation and Grouping

The groups included were a normal control group, a disease controlgroup, a test substance group and a tramadol or morphine group. Otherthan the normal control group, rats were grouped so that the right hindlimb weight load ratio (the measurement of the ratio is describedhereinbelow) of model rats 14 days after induction with MIA generatedaccording to the method as described in the above (1) was equivalentbetween all groups.

(3) Administration of Test Substances, Tramadol or Morphine

The present compounds which are the test substances were respectivelydissolved in Wellsolve (Celeste Corporation) to prepare the solutionswith concentrations of 0.1, 0.3 and 1 mg/mL. The prepared 0.1, 0.3 or 1mg/mL solution was diluted 5-fold with distilled water to prepare 0.02,0.06 or 0.2 mg/mL solution (final concentration of Wellsolve: 20%). Thepositive control drug, tramadol, was dissolved in saline to prepare asolution of 2 mg/mL. Alternatively the positive control drug, morphine,was dissolved in saline to prepare a solution of 0.6 mg/mL. From day 14to day 23 after induction with MIA, a test substance solution (0.1, 0.3or 1 mg/kg) was orally administered to the test substance group twice aday over 10 days. On day 24 after induction with MIA, the test substancesolution was further orally administered 3 hours before the measurementof the right hind limb weight load ratio and saline was subcutaneouslyadministered 1 hour before the measurement. The tramadol group or themorphine group orally received 20% Wellsolve twice a day over 10 daysfrom day 14 to day 23 after induction with MIA. On day 24 afterinduction with MIA, 20% Wellsolve was further orally administered 3hours before the measurement of the right hind limb weight load ratioand a tramadol solution (10 mg/kg) or a morphine solution (3 mg/kg) wassubcutaneously administered 1 hour before the measurement. The normalcontrol group and the disease control group received 20% Wellsolve twicea day over 10 days from day 14 to day 23 after induction with MIA. Onday 24 after induction with MIA, 20% Wellsolve was further orallyadministered 3 hours before the measurement of the right hind limbweight load ratio and saline was subcutaneously administered 1 hourbefore the measurement.

(4) Measurement of Right Hind Limb Weight Load Ratio

The weight load on right and left hind limbs was measured with theLinton Incapacitance Tester (MJS Technology INC., UK). Namely, a rat wastransferred into a cage of the Linton Incapacitance Tester and adjustedso that right and left hind limbs were respectively on each of a pair ofgravimetric sensors. After confirming that the rat was balanced on leftand right and forward and back, the weight load of left and right hindlimbs was respectively measured for 3 seconds. The measurement wasrepeated 3 times per rat. In order to obtain stable results, rats wereconditioned in the cage for 20 minutes or longer per day over 5 or moredays between the day of induction with MIA and day 14 after induction.Further, rats were also conditioned in the cage immediately before themeasurement for about 10 minutes. The weight load of right and left hindlimbs was measured before grouping on day 14 after induction with MIAand day 24 after induction for the normal control group, the diseasecontrol group, the test substance group (3 hours after administration),the tramadol group (1 hour after administration) and the morphine group(1 hour after administration). Based on the averages of right and lefthind limb weight loads, the right hind limb weight load ratio withrespect to the weight load of both hind limbs was calculated accordingto the following Equation 4. The measurement was carried out in a blindmanner. The percent improvement for the present compounds which are thetest substances was calculated based on the right hind limb weight loadratio of each group at day 24 after induction with MIA according to thefollowing Equation 5, thereby evaluating analgesic effect of the testsubstances (present compounds).Right hind limb weight load ratio B(%)={A _(R)/(A _(R) +A_(L))×100}  [Eq. 4]

wherein:

A_(R): weight load of right hind limb (average of three measurements perrat); and

A_(L): weight load of left hind limb (average of three measurements perrat).Percent improvement of test substance (%)={(1−(B _(T) −B _(C))/(B _(N)−B _(C))}×100  [Eq. 5]

wherein:

B_(C): average of the normal control group;

B_(N): average of the disease control group; and

B_(T): average of the test substance group.

As a result, the present compounds had percent improvement that wasequivalent to or higher than that of tramadol and morphine which arecommonly used as analgesic agents. Accordingly, it was found that thepresent compounds had analgesic effect that was equivalent or superiorto tramadol and morphine.

Examples of the analgesic effect (percent improvement) of some of thepresent compounds on MIA-induced model rats are shown in the followingTable 7 (the results obtained with the positive control drug oftramadol) and Table 8 (the results obtained with the positive controldrug of morphine).

TABLE 7 Example Percent improvement (%) 7  61  8-1 60 14-5 47 15-6 5121-9 64  21-13 66 Positive control drug Percent improvement (%) Tramadol43

TABLE 8 Example Percent improvement (%) 14-6  53 15-52 60 15-55 62 15-6353 15-77 55 15-87 57 15-98 57  15-104 54 21-37 67 21-51 68 21-70 6121-73 62 Positive control drug Percent improvement (%) Morphine 54

FORMULATION EXAMPLES Formulation Example 1

The following components were mixed and compressed to tablets accordingto a conventional method to give 10,000 tablets containing 10 mg of theactive ingredient per tablet.

1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin- 100 g5-yl)-3-(2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea Calcium carboxymethylcellulose(disintegrating agent) 20 g Magnesium stearate (lubricant) 10 gMicrocrystalline cellulose 870 g

Formulation Example 2

The following components were mixed according to a conventional method,filtered through a dust filter, distributed to ampoules at 5 ml andthermally sterilized in an autoclave to obtain 10,000 ampoulescontaining 20 mg of the active ingredient per ampoule.

1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin- 200 g5-yl)-3-(2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea Mannitol 20 g Distilled water 50 L

INDUSTRIAL APPLICABILITY

The present compound has Trk-inhibiting activity and thus is useful forprophylaxis and/or therapy of diseases to which Trk is involved, forexample, pain, pruritus, lower urinary tract dysfunction, asthma,allergic rhinitis, inflammatory bowel disease and Chagas disease.

The invention claimed is:
 1. A method for prophylaxis and/or treatment of pain comprising, administering to a patient an effective amount of 1-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea or a salt thereof.
 2. The method according to claim 1, wherein the pain is selected from the group consisting of pain of osteoarthritis, cancer pain, chronic low back pain, low back pain of osteoporosis, pain of bone fracture, pain of rheumatoid arthritis, neuropathic pain, postherpetic pain, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, postoperative pain and pain of pulpitis.
 3. The method according to claim 1, wherein the pain is pain of osteoarthritis.
 4. The method according to claim 1, wherein the pain is cancer pain.
 5. The method according to claim 1, wherein the pain is chronic low back pain.
 6. The method according to claim 1, wherein the pain is low back pain of osteoporosis.
 7. The method according to claim 1, wherein the pain is pain of bone fracture.
 8. The method according to claim 1, wherein the pain is pain of rheumatoid arthritis.
 9. The method according to claim 1, wherein the pain is neuropathic pain.
 10. The method according to claim 1, wherein the pain is postherpetic pain.
 11. The method according to claim 1, wherein the pain is pain of diabetic neuropathy.
 12. The method according to claim 1, wherein the pain is fibromyalgia.
 13. The method according to claim 1, wherein the pain is pain of pancreatitis.
 14. The method according to claim 1, wherein the pain is pain of interstitial cystitis.
 15. The method according to claim 1, wherein the pain is pain of endometriosis.
 16. The method according to claim 1, wherein the pain is pain of irritable bowel syndrome.
 17. The method according to claim 1, wherein the pain is migraine.
 18. The method according to claim 1, wherein the pain is postoperative pain.
 19. The method according to claim 1, wherein the pain is pain of pulpitis. 